The impact of exhaustive exercise on myocardial function is poorly understood. Experimental parameters of contractility that are completely devoid of other influences do not exist. Furthermore, the problem is compounded by the fact that exhaustive work comprises myriad exercise paradigms and fatigue may be the result of numerous possible mechanisms. Despite these confounding variables, there is evidence that stroke volume may be impaired by prolonged work in humans. These studies implicated reduced venous return and not contractility as the reason. Experiments with the rat model have indicated that treadmill running at about 60% of VO2max results in reduced isometric twitch tension in isolated trabecular tissue. The data are consistent with the notion that contractility is substantially reduced. The mechanism for this inhibition is unknown. In separate studies using a similar model, it has been shown that Ca2+ uptake by the sarcoplasm reticulum of the myocardium in vitro is reduced by fatigue. It is conceivable that in exhaustive exercise, there may be only a slight effect on contractility in vivo but that substantial adjustments in intracellular homeostasis are required in order to achieve this. Future considerations should include a rigorous analysis of contractility and the factors that regulate it, as well as the choice of animal and exhaustion models.