Therapeutic phlebotomy remains a key intervention in the management of erythrocytosis and iron overload disorders, particularly polycythemia vera (PV) and hereditary hemochromatosis. Despite its historical origins as an ancient practice, venesection continues to be recommended in international guidelines for the reduction of hematocrit and iron burden, thereby mitigating thrombotic and organ-related complications. However, the evolving landscape of targeted pharmacologic therapies is reshaping the therapeutic paradigm. This review examines the current role of therapeutic phlebotomy, with a particular focus on PV, outlining its physiological rationale, clinical benefits, and well-documented limitations-including iron deficiency, procedural burden, and incomplete hematocrit control between sessions. Comparative insights are provided between phlebotomy and red cell apheresis, highlighting differences in efficacy, tolerability, and accessibility. The emergence of disease-modifying agents-such as interferons, JAK inhibitors, hepcidin mimetics, and epigenetic modulators like givinostat and bomedemstat-promises more sustained hematologic control with the potential to reduce or eliminate the need for repeated phlebotomies. While phlebotomy remains indispensable in early-stage or low-risk PV, its future utility will likely shift toward complementary or bridge therapy in the context of individualized, pharmacologically driven strategies, redefining the role of phlebotomy in the era of precision medicine.