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Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept., Competing Interests: Conflict of interest: L.B. is supported by unrestricted grants form Astra Zeneca. A.D. is co-founder of InVitroSys GmbH, a start-up developing equipment for biomimetic tissue culture. T.E. is co-founder of EHT Technologies GmbH, a university spin-off providing equipment for the generation of EHT. P.F. is the founder and CEO of Pharmahungary Group, a group of R&D companies. L.F. has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (UK), DFG and several biomedical companies. L.F. is listed as inventor of two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571 and Markers for Atrial Fibrillation WO 2016012783). L.F. has served on the Roche Advisory Board on the topic New Biomarkers in Atrial Fibrillation. S.H. is independent consultant or receives research grant from to Astra Zeneca, Bayer, Merck, and Pfizer. The APHP, which employs J.-S.H., has received research grants from Bioserenity, Sanofi, Servier and Novo Nordisk. J.-S.H. has received speaker, advisory board or consultancy fees from Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Novartis, Novo Nordisk, and WeHealth. The UMCU, which employs L.W.v.L. has received speaker, advisory board or consultancy fees and/or research grants from Abbott, Vifor, Novartis, Medtronic, Roche, and Sopachem. J.L. has received research grants from Medtronic. P.v.d.M. received consultancy and/or research grants from Vifor Pharma, AstraZeneca, Servier, Novartis, Pfizer, Ionis. R.P. is co-founder of Pluriomics (Ncardia) and River BioMedics. R.S. received speaker fees from Amgen, Recordati and Sanofi and research grants from Sanofi. T.T. filed and licensed patents in the filled of non-coding RNAs. T.T. is founder and shareholder of Cardior Pharmaceuticals, a clinical-stage biotech company. T.T. received support and/or holds advisory seats at Boehringer Ingelheim, Novo Nordisk, Sanofi-Genzyme, Takeda, Amicus Therapeutics. All other authors have declared no conflict of interest., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)