The intermediate-conductance Ca2+-activated K+ channel (KCa3.1) was first described by Gardos in erythrocytes and later confirmed to play a significant role in T-cell activation and the immune response. More recently, KCa3.1 has been characterized in numerous cell types which contribute to the development of vascular disease, such as T-cells, Bcells, endothelial cells, fibroblasts, macrophages, and dedifferentiated smooth muscle cells (SMCs). Physiologically, KCa3.1 has been demonstrated to play a role in acetycholine and endothelium-derived hyperpolarizing factor (EDHF) induced hyperpolarization, and thus control of blood pressure. Pathophysiologically, KCa3.1 contributes to proliferation of T-cells, B-cells, fibroblasts, and vascular SMCs, as well as the migration of SMCs and macrophages and platelet coagulation. Recent studies have indicated that blockade of KCa3.1, by specific blockers such as TRAM-34, could prove to be an effective treatment for vascular disease by inhibiting T-cell activation as well as preventing proliferation and migration of macrophages, endothelial cells, and SMCs. This vasculoprotective potential of KCa3.1 inhibition has been confirmed in both rodent and swine models of restenosis. In this review, we will discuss the physiological and pathophysiological role of KCa3.1 in cells closely associated with vascular biology, and the effect of KCa3.1 blockers on the initiation and progression of vascular disease.