The voltage‐gated Kv1.3 and the calcium‐activated KCa3.1 potassium channel modulate many calcium‐dependent cellular processes in immune cells, including T‐cell activation and proliferation and have therefore been proposed as novel therapeutic targets for immunomodulation. Kv1.3 is highly expressed in CCR7− effector memory T cells and is emerging as a target for T‐cell‐mediated diseases like multiple sclerosis, rheumatoid arthritis, type‐1 diabetes mellitus, allergic contact dermatitis, and psoriasis. In contrast, KCa3.1 is expressed in CCR7+ naive and central memory T cells, as well as in mast cells, macrophages, dedifferentiated vascular smooth muscle cells, fibroblasts, vascular endothelium, and airway epithelium. Given this expression pattern, KCa3.1 is a potential therapeutic target for conditions ranging from inflammatory bowel disease, multiple sclerosis, arthritis, and asthma to cardiovascular diseases such as atherosclerosis and post‐angioplasty restenosis. Results from animal studies have been supportive of the therapeutic potential of both Kv1.3 and KCa3.1 blockers and have also not shown any toxicities associated with pharmacological Kv1.3 and KCa3.1 blockade. To date, two compounds targeting Kv1.3 are in preclinical development, but so far, no Kv1.3 blocker has advanced into clinical trials. KCa3.1 blockers, on the other hand, have been evaluated in clinical trials for sickle cell anemia and exercise‐induced asthma, but have so far not shown efficacy. However, the trial results support KCa3.1 as a safe therapeutic target and hopefully will enable clinical trials for other medical conditions that might benefit from KCa3.1 blockade. Drug Dev Res 72:573–584, 2011. © 2011 Wiley Periodicals, Inc.