The reviewed studies support the contention that during the high flow or hyperdynamic phase of gram-negative septicemia, cardiac reserve is compromised because of intrinsic myocardial dysfunction. The latter is not referable to coronary hypoperfusion or peripheral pooling or decreased venous return. Although, under resting, nonstressed conditions, indices of myocardial function may appear normal or even elevated, a decreased reserve is evident when additional stress is imposed on the myocardium. Hearts removed from septic rats during the hyperdynamic stage and perfused in vitro (using the isolated perfused working heart preparation) showed a rightward and downward shift in work function curves, indicating a severe depression in cardiac function. Possible mechanisms for the observed dysfunction are discussed. No significant alterations in high energy phosphate production or substrate utilization were observed, indicating that altered myocardial metabolism is not likely to be a significant contributor to the dysfunction. Our results suggest that cardiac dysfunction is partially due to an elevation in the cytosolic calcium concentration which may slow the rate of ventricular relaxation. These studies emphasize that intrinsic cardiac function is depressed early during the course of the septic episode at a time that precedes the onset of circulatory shock.