Skeletal muscle plays a fundamental role in human health and so understanding the biological processes that regulate skeletal muscle mass in health and disease is critical. We know that resistance exercise increases rates of muscle protein synthesis (MPS) in a mechanistic target of rapamycin complex 1 (mTORC1)-dependent manner. However, the exact molecule(s) that ‘sense’ mechanical loading and translate that signal to a biochemical event leading to upregulation of MPS remains elusive. Similarly, in response to periods of unloading there is a decrease in MPS and potentially a transient increase in muscle protein breakdown MPB, but the relative contribution of MPS and MPB to muscle atrophy remains unknown. The aim of this review is to briefly outline the molecular mechanisms that regulate skeletal muscle protein mass in response to both mechanical loading and unloading (disuse). We discuss recent developments in the field of molecular exercise biology as well as present a working hypothesis as to the physiological basis for muscle disuse atrophy.