The reigning paradigm of rational drug discovery in translational medicine attempts to exploit biological theories and pathophysiological explanations to identify novel drug targets and therapeutic strategies. Yet because many theories in medicine are either incomplete (at best) or false (at worst), relying on theoretical explanations can have some puzzling and troubling consequences. New drugs may be shown to be effective in clinical trials and receive regulatory approval despite a faulty explanation for why they are effective. If physicians rely on this explanation to make treatment decisions, it can lead to systematic misdiagnoses and patient harm. For research programs, underdetermination may shield faulty biomedical explanations, and this can result in wasted research resources and avoidable burdens on human subjects. These problematic features of biomedical explanations can be resolved by reconceiving the epistemology of translational medicine in terms of heuristics.