In human T-lymphocytes, the voltage-gated Kv1.3 channel and the Ca(2+)-activated IKCa1 channel play an important role in Ca2+ signaling, activation, adhesion and migration and have, therefore, long been regarded as attractive targets for immunotherapy. Here, we review the pharmacology of the two channels, their expression pattern in naïve and memory T-cells and their functional roles during T-cell activation, and explain the rationale for the use of Kv1.3 blockers for the therapy of T-cell mediated autoimmune diseases.