Extensive injury of endothelial cells in blood vasculature, especially in the microcirculatory system, frequently occurs in hosts suffering from sepsis and the accompanied systemic inflammation. Pathological factors, including toxic components derived from invading microbes, oxidative stress associated with tissue ischemia/reperfusion, and vessel active mediators generated during the inflammatory response, are known to play important roles in mediating endothelial injury. Collapse of microcirculation and tissue edema developed from the failure of endothelial barrier function in vital organ systems, including the lung, brain, and kidney, are detrimental, which often predict fatal outcomes. The host body possesses a substantial capacity for maintaining vascular homeostasis and repairing endothelial damage. Bone marrow and vascular wall niches house endothelial progenitor cells (EPCs). In response to septic challenges, EPCs in their niche environment are rapidly activated for proliferation and angiogenic differentiation. In the meantime, release of EPCs from their niches into the blood stream and homing of these vascular precursors to tissue sites of injury are markedly increased. The recruited EPCs actively participate in host defense against endothelial injury and repair of damage in blood vasculature via direct differentiation into endothelial cells for re-endothelialization as well as production of vessel active mediators to exert paracrine and autocrine effects on angiogenesis/vasculogenesis. In recent years, investigations on significance of EPCs in host defense and molecular signaling mechanisms underlying regulation of the EPC response have achieved substantial progress, which promotes exploration of vascular precursor cell-based approaches for effective prevention and treatment of sepsis-induced vascular injury as well as vital organ system failure.