The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago [180]. Despite extension of the concept to ischemic postcondition‑ing [460] and remote ischemic conditioning [202, 344] and literally thousands of experimental studies in various spe‑cies and models which identified a multitude of signaling steps [199], so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients [155, 200]. Many potential reasons for this disap‑pointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies [54, 195], and poor design and conduct of clinical trials [196, 206]. There is, however, universal agree‑ment that robust preclinical data are a mandatory prerequi‑site to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi‑center approach of preclini‑cal studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size [230]. However, ischemic precondition‑ing—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction [181, 197, 203]. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can sub‑sequently be tested in clinical trials must be developed [184]. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction [279], and aim to pro‑vide now practical guidelines to ensure rigor and reproduc‑ibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [279], we define rigor as standardized state‑of‑the‑art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, ie replication of results by another laboratory when per‑forming exactly the same experiment.