The Ca(2+)-activated K(+) channel K(Ca)3.1 regulates membrane potential and calcium signaling in erythrocytes, activated T and B cells, macrophages, microglia, vascular endothelium, epithelia, and proliferating vascular smooth muscle cells and fibroblasts. K(Ca)3.1 has therefore been suggested as a potential therapeutic target for diseases such as sickle cell anemia, asthma, coronary restenosis after angioplasty, atherosclerosis, kidney fibrosis and autoimmunity, where activation and excessive proliferation of one or more of these cell types is involved in the pathology. This article will review the physiology and pharmacology of K(Ca)3.1 and critically examine the available preclinical and clinical data validating K(Ca)3.1 as a therapeutic target.