After years of intense research using structural, biological, and biochemical experimental procedures, it is clear that myosin molecules are essential for striated muscle contraction. However, this is just the tip of the iceberg of their function. Interestingly, recently, it has been shown that these molecules (especially myosin heavy chains) are also crucial for cardiac and skeletal muscle relaxed state. In the present review, we first overview myosin heavy chain biochemical states and how they influence the consumption of ATP. We then detail how neighbouring partner proteins including myosin light chains and myosin binding protein C intervene in such processes, modulating energy demand in health and disease. Finally, we present current experimental drugs targeting myosin ATP consumption and how they can treat muscle diseases.