Macrophages play an important role in brain immune and inflammatory responses. They are also critical cells in mediating the pathology of neurodegenerative disorders such as HIV-associated dementia. This is largely through their capacity to secrete a variety of bioactive molecules such as cytokines, leading to neuronal dysfunction and/or death. Accumulating evidence indicates that voltage-gated potassium (Kv) channels play a pivotal role in the modulation of macrophage proliferation, activation, and secretion. Blockade of Kv channels by specific antagonists decreases macrophage cytokine production and ameliorates macrophage-associated neuronal injury. These results suggest that Kv channels might become a potential target for the development of new therapeutic strategies for chronic inflammatory diseases.