Adjunctive cardioprotective strategies for ameliorating the reversible and irreversible injuries with ischemia-reperfusion (I/R) are highly desirable. However, after decades of research the promise of clinical cardioprotection from I/R injury remains poorly realized. This may arise from the challenges of trialing and effectively translating experimental findings from laboratory models to patients. One can additionally consider whether features of the more heavily focused upon candidates could limit or preclude therapeutic utility, and thus whether we might shift attention to alternate strategies. The phenomena of preconditioning (Precon) and postconditioning (Postcon) have proven fertile in identification of experimental means of cardioprotection, and are the most intensely interrogated responses in the field. However, there is evidence these processes, which share common molecular signaling elements and end-effectors, may be poor choices for clinical exploitation. This includes evidence of: age-dependence, limiting efficacy in target aged or senescent hearts; refractoriness to conditioning stimuli in diseased myocardium; interference from a variety of relevant pharmaceuticals; inadvertent induction of these responses by prior ischemia or commonly employed drugs, precluding further benefit; and sex dependence of protective signaling. This review focuses on these features, raising questions about current research strategies, and the suitability of these widely studied phenomena as rational candidates for clinical translation.