At the one year anniversary of his death, it is fitting to pay tribute to the life and science of Sir James W. Black, a man whose work transformed the fields of medicine and pharmacology. In this special issue of Trends in Pharmacological Sciences, we examine various areas of research that were near and dear to Sir James's heart.Many of the contributors to this special edition were privileged to spend time in the company of Sir James, some as students at the beginning of their careers, others as established researchers in academia and the pharmaceutical industry. Sir James’ career was spent traversing the industry and academia. Indeed, he occasionally referred to his academic laboratory at King's College, the Department of Analytical Pharmacology, and interactions with academics as a source of ‘intellectual oxygen’. However, he was perhaps at his most inspiring when in the midst of multidisciplinary drug discovery and development project teams. As a true polyglot, he reveled in the company of medicinal chemists and the myriad other specialists gathered to solve problems and progress projects. He had an instinct for identifying and engaging those who could bring a new technique or analytical approach to address the problem with which he was wrestling.Sir James also had a passion for music, art and language. His dictionary was always close at hand as he sought to express ideas and concepts with precision. In many ways he was a master storyteller, when lecturing or when painstakingly preparing review articles and manuscripts. His own account of the work that led to the award of the Nobel Prize [1xSee all References][1] provides an insight into how each series of experiments and discoveries, in the context of the work of others, was a continual intellectual journey based on hypothesis building, testing and reformulating.Although his influence is far-reaching, Sir James is best known for three main contributions to science and medicine: (i) his pioneering work in rational drug design, (ii) his study of β-adrenoceptor pharmacology that led to the development of propranolol and (iii) his research on histamine receptor pharmacology that led to the development of cimetidine. The authors herein examine Black's contributions to each of these areas and put them in a modern context.First, in an opinion article, Michael Walker explores the question: what is the best way to measure the life of a man who changed medicine? The article includes some highlights of Black's illustrious career.In the next series of opinion articles, Terry Kenakin and Arthur Christopoulos discuss the key principles of analytical pharmacology, both as they were envisioned by Black and how they are used today. Clive Page provides a different slant with his discussion of ‘paradoxical pharmacology’ and how receptor–ligand interactions are more complex than Black could have appreciated when he started his research in the field.Despite his success and recognition, Sir James would always prioritize the discussion of new data (‘bring me the experimental traces’) and the opportunity to spend time with students and those working hands-on in the laboratory. In the final opinion article, two of his most recent PhD students, Magda Morton and Clodagh Prendergast, contribute together with Terrance Barrett to a discussion of an area of research that was exciting Black near the end of his career: the promise of blocking CCK2 receptors for the treatment of gastroesophageal reflux disorder (GERD) and gastrointestinal adenocarcinomas.The first set of reviews focuses on beta-blockers and β-adrenoceptor (βAR) pharmacology. Beta-blockers remain mainstays of treatment in heart disease, and in recent years have enjoyed a new life as a treatment for chronic heart failure (CHF). Sverre Kjeldsen and colleagues review the results of large randomized placebo-controlled clinical trials that have changed the mind of physicians about the benefits of beta-blocker therapy for CHF. Next, Brian Kobilka reviews recent insights into βAR pharmacology that have emerged from the characterization of the three-dimensional structures of βARs in both active and inactive states. In their review, Craig Daly and John C. McGrath examine how the discovery of βARs in previously unsuspected cell types is contributing to the rethinking of new drug targets. Finally, Jillian Baker, Stephen Hill and Roger Summers examine emerging principles of β-adrenoceptor pharmacology, including the importance of receptor subtype selectivity and ligand-directed signaling.In a related article, James Angus, Paul Korner and Christine Wright review examples of how elucidation of complex physiological control mechanisms (such as in blood vessels) is greatly facilitated by the complete characterization of concentration–effect curves and by the application of analytical pharmacology.The second set of reviews explores the renewed interest in histamine receptor antagonism. In their search for a histamine antagonist that would treat peptic ulcers, Black and colleagues developed burimamide, a compound that eventually led to cimetidine. However, burimamide was instrumental in the discovery of a third histamine receptor, H3R, because it proved to be much more selective for H3R than H2R. Maria Beatric Passani and Patrizio Blandino review current knowledge of H3R pharmacology and examines some of the potential therapeutic indications for targeting this receptor in the central nervous system. Rob Leurs and colleagues discuss how advances in molecular biology have helped drive the histamine field, permitting the development of novel ligands for H3R and H4R. These compounds offer new possibilities for the treatment of diseases ranging from narcolepsy and pain to obesity and allergic diseases.Finally, we examine how treatment of GERD has changed since the discovery of cimetidine. Cimetidine and related compounds were eventually supplanted by the development of proton pump inhibitors (PPIs). Despite the success of PPIs, there are remaining unmet needs in the treatment of gastrointestinal reflux disorders. Tiberiu Hershcovici and Ronnie Fass review current and emerging treatments for GERD.We chose to end with a quote from Sir James [2xPharmacology: analysis and exploration. Black, J.W. BMJ. 1986; 293: 252–255Crossref | PubMed | Scopus (6)See all References][2] that perhaps best summarizes his approach to the integration of basic science with the art of drug discovery:‘Experimenting would be boring if we never got surprises. We get surprises when we find something we did not expect. Expectation means that we had a rule or an idea or a model in our heads before we started. Our prior conception deals with a surprise by accommodation or adjustment, usually by muttering something such as: “X is behaving as though Y had happened.” Whenever we use such a simile to describe experience we usually express what we have said by some kind of mathematical equivalent-that is, an operational model. Making models forces us to shed woolliness in our thinking. In this form the idea is easier to challenge and to test experimentally. The strategy is to estimate model parameters, which have chemical meaning, from estimations of assay parameters, which do not have chemical meaning. Measurement of the full range of the concentration-response curves to get estimates of their parameters -that is, location, slope, asymptote-is therefore needed. More importantly, however, the ability of bioassays to determine chemical information depends entirely on the quality of the models we use to organise our thought and design our experiments.When drugs are used therapeutically they are often being used to introduce bias into a regulated process. No great precision is needed and a resultant action may not only be adequate but may, indeed, be desirable. When the same substance is used as an exploring ligand, however, it may simply lack the authority because of imprecision, resultant activity recognised or unrecognised, or the lack of appropriate modelling. Drugs are neither physicians’ scalpels nor biophysicists’ lasers. As with much else in life, the usefulness of drugs is a function of the care and attention we pay to them.’Trends in Pharmacological Sciences would like to thank the Guest Editors and all of the contributors to this special issue, the authors and the referees, for making this issue possible, and we hope you enjoy the articles as much as we did.