Although cardiac output is measured as the flow of blood from the left ventricle into the aorta, the system that controls cardiac output includes many other components besides the heart itself. The heart’s rate of output cannot exceed the rate of venous return to it, and therefore, the factors governing venous return are primarily responsible for control of output from the heart. Venous return is affected by its pressure gradient and resistance to flow throughout the vascular system. The pressure gradient for venous return is a function of several factors including the blood volume flowing through the system, the unstressed vascular volume of the circulatory system, its capacitance, mean systemic pressure, and right atrial pressure. Resistance to venous return is the sum of total vascular resistance from the aortic valve to the right atrium. The sympathetic nervous system and vasoactive circulating hormones affect short-term resistance, whereas local tissue blood flow autoregulatory mechanisms are the dominant determinants of long-term resistance to venous return. The strength of contraction of the heart responds to changes in atrial pressure driven by changes in venous return, with small changes in atrial pressure eliciting large changes in strength of contraction, as described by the Frank–Starling mechanism. In addition, the autonomic nervous system input to the heart alters myocardial pumping ability in response to cardiovascular challenges. The function of the cardiovascular system is strongly affected by the operation of the renal sodium excretion–body fluid volume–arterial pressure negative feedback system that maintains arterial blood pressure at a controlled value over long periods. The intent of this volume is to integrate the basic knowledge of these cardiovascular system components into an understanding of cardiac output regulation.