Despite a growing body of evidence suggesting that prolonged strenuous exercise (PSE) is associated with a transient reduction in right (RV) and left ventricular (LV) performance, the exact mechanism(s) responsible for this phenomenon is not fully understood. As such, the primary objective of this article was to critically review the available literature (both animal and human) to provide insight into the potential mechanism(s) responsible for the development of "exercise-induced cardiac fatigue." We pay particular attention to the major mechanisms that have been linked to transient changes in systolic function after PSE including altered loading conditions, myocardial ischemia/damage, altered β-receptor responsiveness, and altered cardiac autonomic modulation. We also examine the potential mechanisms that may contribute to transient changes in diastolic function often observed after PSE including changes in LV pressure gradients and alterations in intrinsic myocardial relaxation. Although further mechanistic investigations are clearly warranted, several key mechanisms have received support for at least a partial contribution to the transient changes in myocardial performance often observed after PSE.