The force-interval relationship is an important modulator of contractility in mammalian myocardium. In a number of mammalian species, increasing the frequency of stimulation results in an increase in force of contraction. Over the last 10 years, the effects of atrial pacing have been closely examined in normal human subjects and in patients with dilated cardiomyopathy, and the effects of the stimulation frequency have been investigated in isolated preparations from nonfailing and failing human hearts. An abnormal force-interval relationship in vivo and in vitro has been a consistent finding in patients with dilated cardiomyopathy, whereby an increase in stimulation frequency fails to increase the contractile response. The force-interval relationship of cardiac muscle has been shown to reflect intracellular calcium cycling and sarcoplasmic reticulum function. Therefore, agents that affect excitation-contraction coupling, in particular intracellular calcium mobilization and sarcoplasmic reticulum function, modulate the response of contraction force to stimulation frequency.