For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.