The functional significance of the Frank-Starling mechanism under physiological and pathophysiological conditions is discussed, based mainly on animal experiment results (in the dog, pig and rat). The dependence of individual stroke volume on end-diastolic volume can be described adequately using Frank's diagram. This can be illustrated by varying filling pressure (respiratory cycle, vascular tone in the capacitance system, body position, circulating blood volume) and by alterations in the duration of the filling period (heart rate and rhythm, rate of relaxation) and in ventricular compliance (wall thickness, fibrosis; contracture, rigor). The functional importance of the Frank-Starling mechanism lies mainly in adapting left to right ventricular output. During upright physical exercise an increase in end-diastolic volume due to the action of the peripheral muscle pump and increased venous tone can assist in enhancing stroke volume. Reduced contractility leads to a shift of the operating point to the right in the pressure-volume diagram, thus tending to prevent a decrease in stroke volume. However, the consequences of increased circulating blood volume in chronic heart failure are, as a rule, mainly detrimental (congestive symptoms; myocardial component of coronary resistance; cardiac energetics). Reduced contractility results in a flattening of the relation between stroke volume (or stroke work) and end-diastolic volume. Furthermore, the Starling mechanism is prevented from becoming effective if the sarcomere-length reserve is exhausted, or in the presence of inadequate sarcomere extension due to impaired relaxation or reduced distensibility of the ventricular wall. The latter is illustrated using the example of a dilated fibrotic left ventricle from a rat with experimental supravalvular aortic stenosis.