Aside from its established immunologic and hematologic functions, the spleen also plays an important role in cardiovascular regulation. This occurs through changes in intrasplenic microvascular tone, as well as through splenic neurohormonal modulation of the renal and mesenteric vascular beds. Splenic regulation of blood volume occurs predominantly through fluid extravasation from the splenic circulation into lymphatic reservoirs; this is controlled by direct modulation of splenic pre- and postcapillary resistance by established physiologic agents such as atrial natriuretic peptide (ANP), nitric oxide (NO), and adrenomedullin (ADM). In addition to physiologic fluid regulation, splenic extravasation is a key factor in the inability to maintain adequate intravascular volume in septic shock. The spleen also controls renal microvascular tone through reflex activation of the splenic afferent and renal sympathetic nerves. This splenorenal reflex not only contributes to the physiologic regulation of blood pressure, but also contributes to the cardiovascular dysregulation associated with both septic shock and portal hypertension. In septic shock, the splenorenal reflex protectively limits splenic extravasation and potentially promotes renal sodium and water reabsorption and release of the vasoconstrictor angiotensin II; this function is eventually overwhelmed as shock progresses. In portal hypertension, on the other hand, the splenorenal reflex-mediated reduction in renal vascular conductance exacerbates sodium and water retention in the kidneys and may eventually contribute to renal dysfunction. Preliminary evidence suggests that the spleen also may play a role in the hemodynamic complications of portal hypertension via neurohormonal modulation of the mesenteric vascular bed. Lastly, the spleen itself may be a source of a vasoactive factor.