Although the utility and benefits of anesthesia and analgesia are irrefutable, their practice is not void of risks. Almost all drugs that produce anesthesia endanger cardiovascular stability by producing dose-dependent impairment of cardiac function, vascular reactivity, and compensatory autoregulatory responses. Whereas anesthesia-related depression of cardiac performance and arterial vasodilation are well recognized adverse effects contributing to anesthetic risk, far less emphasis has been placed on effects impacting venous physiology and venous return. The venous circulation, containing about 65–70% of the total blood volume, is a pivotal contributor to stroke volume and cardiac output. Vasodilation, particularly venodilation, is the primary cause of relative hypovolemia produced by anesthetic drugs and is often associated with increased venous compliance, decreased venous return, and reduced response to vasoactive substances. Depending on factors such as patient status and monitoring, a state of relative hypovolemia may remain clinically undetected, with impending consequences owing to impaired oxygen delivery and tissue perfusion. Concurrent processes related to comorbidities, hypothermia, inflammation, trauma, sepsis, or other causes of hemodynamic or metabolic compromise, may further exacerbate the condition. Despite scientific and technological advances, clinical monitoring and treatment of relative hypovolemia still pose relevant challenges to the anesthesiologist. This short perspective seeks to define relative hypovolemia, describe the venous system’s role in supporting normal cardiovascular function, characterize effects of anesthetic drugs on venous physiology, and address current considerations and challenges for monitoring and treatment of relative hypovolemia, with focus on insights for future therapies.