An increasing number of devices can provide mechanical circulatory support (MCS) to patients with acute hemodynamic compromise and chronic end-stage heart failure. These devices work by different pumping mechanisms, have various flow capacities, are inserted by different techniques, and have different sites from which blood is withdrawn and returned to the body. These factors result in different primary hemodynamic effects and secondary responses of the body. However, these are not generally taken into account when choosing a device for a particular patient or while managing a patient undergoing MCS. In this review, we discuss fundamental principles of cardiac, vascular, and pump mechanics and illustrate how they provide a broad foundation for understanding the complex interactions between the heart, vasculature, and device, and how they may help guide future research to improve patient outcomes.