Septic shock is a major cause of morbidity and mortality throughout the world. Source control, antimicrobial therapy, early goal-directed fluid resuscitation, and infusion of vasoactive pharmaceuticals remain the cornerstones of treatment. However, the cardiovascular management of septic shock is evolving. Basic science and clinical researchers have identified novel drug targets and are testing the efficacy of new therapeutic agents. For example, prevention of microvascular leak during septic shock is the focus of active investigations and may soon provide considerable benefit to patients. Among the important topics that will be discussed in this review are the following: the role of vascular endothelial dysfunction in microvascular leak, the impact of cytokines upon structural and functional proteins within the endothelial barrier and within the heart, and the ability of selective vasopressin 1a receptor agonists to minimize tissue edema and improve hemodynamic status.