Objective: The computational ability of the dendrites to process large information depends on the precise localization of ion channels, in the vast, yet compartmentalized dendritic membrane. However, the molecular mechanisms that underlie this demanding task are poorly understood. In this study, we focus on voltage- gated potassium channels, Kv2.1 and Kv4.2, which show extremely distinct localizations within the dendrites of hippocampal pyramidal neurons: Kv2.1 is localized in the proximal part, whereas Kv4.2 shows increasing expression in the distal dendrites. We test the hypothesis that there are multiple different trafficking pathways to deliver ion channels to their distinct destinations in the dendrites. Method: We have employed quantitative live-cell imaging of Kv2.1 and Kv4.2 channel subunits tagged with fluorescent proteins in cultured hippocampal neurons to test the predictions that Kv2.1 and Kv4.2 are sorted into distinct post-Golgi transport vesicles, and that these vesicles are differentially delivered to the distinct domains in the dendrites. Results: Our data demonstrate that Kv2.1 and Kv4.2 channels are sorted in non- overlapping populations of post-Golgi transport vesicles. Furthermore, we have found that vesicles carrying Kv2.1 are transported by the non-muscle myosin II motor on F-actin, whereas Kv4.2 vesicles depend on the microtubule-kinesin transport system. Finally, our results show that sorting and trafficking properties of Kv2.1 and Kv4.2 are dramatically affected by mutating their peptide targeting motifs, which have been shown to be essential for their distinct steady- state localizations. Conclusion: Sorting into distinct populations of vesicles as well as trafficking by distinct mechanisms contributes to the restricted localization of Kv2.1 and Kv4.2 channels within the somatodendritic compartment of neurons.