Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies., Competing Interests: Declaration of interests KGB declares institutional grant funding from Rocket Medical and RS Oncology; lecture honoraria from Bristol-Myers Squibb; and the role of chief investigator of the PREDICT-Meso International Accelerator Network. PSA declares research funding from ATARA Biotherapeutics; patents, royalties, and intellectual property on therapies licensed to ATARA Biotherapeutics; and scientific advisory board membership and consulting fees from ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion Pharma, and Outpace Bio. PA declares equipment loans for courses from Novatech, Wolf, and Olympus. LD declares lecture honoraria from Bristol-Myers Squibb. YCGL declares receipt of equipment from Rocket Medical for use in clinical trials. ASM declares institutional grant funding from Novartis and Verily; consulting fees from Rising Tide and TRIPTYCH Health Partners; institutional payments or honoraria from Janssen, BeiGene, Chugai Pharmaceutical (Roche), Ideology Health (formerly Health Media), Antoni van Leeuwenhoek Kanker Instituut, AXIS Medical Education, Johnson & Johnson Global Services, Intellisphere, Answers in CME, University of Miami International Mesothelioma Symposium, and Immunocore; support for attending meetings from Shanghai Roche; membership of scientific advisory boards for AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Takeda Oncology, and Sanofi Genzyme; and study funding from Bristol-Myers Squibb. SJM is co-principal investigator of the Engineering and Physical Sciences Research Council Interdisciplinary Research Collaboration in Targeted Delivery for Hard-to-Treat Cancers; he declares consulting fees from DefiniGEN, and support for attending meetings from Alpha-1 Foundation, Federation of American Societies for Experimental Biology, and Mesothelioma UK. NM declares consulting fees from Rocket Medical UK, Cook Medical UK, and Becton Dickinson. VP declares grant funding from the Danish Comprehensive Cancer Center and no conflicts of interest within the scope of this Viewpoint. NMR declares consulting fees from Rocket Medical UK, Cook Medical UK, and LTI USA. MGZ declares institutional grant funding from Medimmune, Precog, GSK, Epizyme, Polaris, Sellas Life Sciences, Bristol-Myers Squibb, Millenium, Curis, and Atara; consulting fees from Curis, Ikena, Takeda, GSK, and Novocure; and honoraria from PER and Medscape. DS declares support including research funding and consulting fees from AstraZeneca, Boehringer Ingelheim, Exigo Management, Flame Biosciences, HitchBio, Intuitive Surgical, Janssen, Johnson & Johnson, Medscape, Olympus Corporation of the Americas (also known as Spiration), Sensei Biotherapeutics, Trizell, Trustees of the University of Pennsylvania, Verismo, and Wolters Kluwer Health. DAF declares institutional grants from Aldeyra, Astex Therapeutics, Bayer Oncology, Bergen Bio, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Lovance, MSD, Owkin, Roche Oncology, and RS Oncology; consulting fees from Cambridge Clinical Laboratories and RS Oncology; honoraria from MSD and Bristol-Myers Squibb; support for attending meetings from RS Oncology; and participation on data monitoring or advisory boards for AstraZeneca and RS Oncology. TP declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)