Differential sub-cellular distribution and voltage-dependent gating properties of Kv channels are crucial for the regulation of neuronal excitability. In mammalian central neurons, the majority of delayed-rectifier K+ currents (IK) are contributed by Kv2.1 channels, and Kv4.2 and Kv4.3 channels constitute most of the A-type K+ currents (IA) in the soma and dendrites. Kv2.1 channels are localized in distinct cell surface clusters in the soma and proximal dendrites, a pattern conserved in recombinant channels expressed in HEK293 cells. This clustering is dependent on the extent of channel phosphorylation. Our recent studies have shown that the clustered localization and gating properties of Kv2.1 are dynamically regulated by altered neuronal activity, ischemia, and by neuromodulatory stimuli via Ca2+/calcineurin-mediated dephosphorylation of the channel protein. These changes in Kv2.1 play a neuroprotective role. A number of studies have proposed the association of Kv2.1 with caveolar lipid rafts. We observed that Kv2.1 clusters in HEK293 cells do not overlap with caveolin1- or flotillin1/2-containing lipid rafts/microdomains on the cell surface. Moreover, caveolin1 staining/puncta were detected only in cultured rat astrocytes/glia, not in cultured rat hippocampal neurons. Caveolin1-RFP, overexpressed both in HEK293 cells stably expressing Kv2.1, and in cultured hippocampal neurons, exhibited distinct surface puncta that did not overlap with Kv2.1 clusters, and also did not alter the current density and voltage-dependent channel gating properties. Cyclodextrin-induced disruption of lipid rafts did not alter the clustered localization of Kv2.1 in HEK293 cells. Similarly, the staining pattern of Kv4.2 and Kv4.3 channels with or without the overexpression of KChIP2 did not overlap with caveolin1- and flotillin1/2-containing lipid rafts/microdomains in HEK293 and COS cells. These results suggest that in mammalian central neurons, somatodendritic Kv channels are not recruited to, and function independently of, lipid rafts/microdomains.