Various human diseases can disrupt the balance between muscle contraction and relaxation. Sarcomeric modulators can be used to readjust this balance either indirectly by intervening in signalling pathways or directly through interaction with the muscle proteins that control contraction. Such agents represent a novel approach to treating any condition in which striated muscle function is compromised, including heart failure, cardiomyopathies, skeletal myopathies and a wide range of neuromuscular conditions. Here, we review agents that modulate the mechanical function of the sarcomere, focusing on emerging compounds that target myosin or the troponin complex.