The past decade has witnessed growing scientific and commercial interest in the identification of bioactive oral compounds that mimic or potentiate the effects of exercise, so-called ‘exercise pills’ or ‘exercise mimetics.’ These compounds have, to date, typically targeted skeletal muscle in an attempt to stimulate some of the adaptations to exercise induced by endurance training. Accordingly, they fail to impart many of the broad health protecting effects of exercise that are seen in tissues and organs other than skeletal muscle. In the context that multiple integrative regulatory and often redundant pathways have evolved to detect and respond to human movement, here we consider the complex challenges of designing a pill that might mimic the extensive range of exercise benefits. In particular, we consider the limits of the current ‘myocentric’ paradigm given the wide-ranging array of impacts that exercise exerts on atherosclerosis and the cardiovascular system. We discuss the validity and limitations of the concept that low dose cardiovascular polypills, already in large scale trials, may represent one form of cardiovascular exercise mimetic. Finally, given that some calls for an exercise pill stem from a response to the perceived failure of expert advice, evidence-based guidelines and current public health approaches, we explore possible strategies that might address the global rise in inactivity. In the event that a broad spectrum exercise mimetic might ever be developed, we discuss some generic issues related to adoption and adherence of therapeutic interventions.