Clinical trials have demonstrated the adverse long-term effect of inotropic drugs for the treatment of heart failure. Because most of these drugs exert their effects via the increase of intracellular calcium concentration, people have sought a new class of agents working independently of the calcium handling mechanism. We have studied the function of cardiac myosins with various molecular structures to elucidate their role in diseased conditions, but, at the same time, such studies suggested the possible new mechanisms for modulating cardiac contractility at the crossbridge level. Studies on mutant myosins implicated in familial hypertrophic cardiomyopathy, replacement of a single amino-acid located in the C-terminus thus being far from the functional domains responsible for ATP hydrolysis or actin-binding introduced severe functional defect. On the other hand, myosin light chains seem to modulate crossbridge kinetics without changing ATPase activity of myosin. These calcium-independent (downstream) mechanisms for the modulation of cardiac contractility will be discussed with additional observations. [J Physiol Sci. 2006;56 Suppl:S57]