The Kv1.3 and KCa3.1 potassium channels are promising targets for the treatment of autoimmune disorders. Many Kv1.3 and KCa3.1 blockers have a more favorable adverse event profiles than existing immunosuppressants, suggesting the selectivity of Kv1.3 and KCa3.1 blockade. The Kv1.3 and KCa3.1 blockers exert differential effects in different autoimmune diseases. The Kv1.3 inhibitors or gene deletion have been shown to have benefits in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, and rapidly progressive glomerulonephritis. The KCa3.1 blockers have demonstrated efficacy in human primary biliary cirrhosis and showed protective effects in animal models of severe colitis, allergic encephalomyelitis, inflammatory bowel disease, and multiple sclerosis. The KCa3.1 blockers are not considered candidates for treatment of multiple sclerosis. The selective immunosuppressive effects of the Kv1.3 and KCa3.1 blockers are due to the differences in their distribution on autoimmune–related immune cells and tissues and β1 integrin (very late activating antigen)–Kv1.3 channel cross-talk.