Skeletal muscle hypertrophy commonly occurs with repeated bouts of resistance exercise as well as following the administration of exogenous drugs. This increase in muscle size is thought to be mechanistically important for the increase in muscle function. However, at present, there is no experimental evidence that would support any paradigm in which muscle hypertrophy is a mechanism for increasing strength with exercise. Therefore, it seems reasonable to also question the importance of changes in muscle size for changes in muscle strength (function) following exogenous drugs as well as aging, where both muscle size and strength decrease. The purpose of this paper is to discuss whether changes in muscle size contribute to changes in voluntary strength following exercise, pharmaceutical interventions, and aging. We also aim to provide potential mechanisms (central and peripheral) for the change in strength as well as outline study designs to better address this question. Herein, we suggest that there are dissociations between changes in muscle size and strength following exercise, anabolic drug administration, and aging (to a point). These dissociations occur throughout the literature, suggesting that these changes may be completely separate phenomena. We are not dismissing the potential importance of maintaining muscle mass, particularly in clinical populations. What we are suggesting, however, is that muscle function may not necessarily be improved by these exercise or pharmacological induced increases in muscle size. Exploring mechanisms and explanations beyond just changes in muscle size may improve therapy targeted at improving muscle function.