Widespread heart failure has led to increased dependence on left ventricular assist devices (LVAD). However, it is crucial to understand the interaction between the LVAD and the patient’s circulatory system for optimal care and improved outcomes. This chapter on LVAD physiology describes the interdependence of the LVAD and the circulation from the context of LVAD working principles, LVAD speed and pressure-flow relationships. We further describe the physiological underpinnings of hemodynamic optimization including afterload, preload, ventricular contractility, flow pulsatility, LVAD speed, and achieving regular aortic valve opening. Within the same narrative, we provide an in-depth discussion regarding LVAD operation in extreme conditions such as suction events and managing and optimizing LVAD therapy for achieving exercise capacities. We discuss how these factors influence the chronotropic, ionotropic, and vascular responses towards understanding the physiology of LVAD therapy.