A number of pathologic processes contribute to the elevation in cardiac filling pressures in heart failure (HF), including myocardial dysfunction and primary volume overload. In this review, we discuss the important role of the venous system and the concepts of stressed blood volume and unstressed blood volume. We review how regulation of venous tone modifies the distribution of blood between these 2 functional compartments, the physical distribution of blood between the pulmonary and systemic circulations, and how these relate to the hemodynamic abnormalities observed in HF. Finally, we review recently applied methods for estimating stressed blood volume and how they are being applied to the results of clinical studies to provide new insights into resting and exercise hemodynamics and therapeutics for HF.