Phenotypic modulation of VSMCs requires dramatic changes in gene expression profile. These changes involve a switch in ion transport mechanisms, as they are key elements required to redirect cell metabolism to new functional tasks. However, the large diversity of ion channels and the heterogeneity of their expression pattern across different vascular beds has hindered the identification of candidate channels implicated in the phenotypic switch across different VSMCs preparations. The previous work of our group sought to circumvent this limitation by using high-throughput real-time PCR, to obtain a global portrait of ion channel expression in contractile versus proliferating VSMCs. We use several mouse vascular beds and several proliferative models. Changes in mRNA expression showed a good correlation between the two proliferative models, with only two genes, Kv1.3 and Kvbeta2, increasing their expression upon proliferation. In addition, these mRNA changes translate into similar changes in protein expression and function upon proliferation. While in contractile VSMCs Kv1.5-mediated currents are predominant, in proliferating VSMCs Kv1.3 channels are the main contributors to the Kv1-mediated component of the Kv current1. Besides, functional studies show that Kv1.3 current up-regulation in these cells is an essential component of their migratory and proliferative phenotype. The objectives of the present study were twofold: (1) to explore whether this Kv1.3 up-regulation is a conserved landmark of VSMCs proliferation in different vascular beds from different species, and (2) to explore the molecular determinants and the signalling cascade linking the functional expression of Kv1.3 channels to cell proliferation. We have analyzed VSMCs from different human vascular beds. In all cases we found a switch from a predominant expression of Kv1.5 in the contractile phenotype to a predominant expression of Kv1.3 channels in the proliferative phenotype. This Kv1.5 to Kv1.3 switch is functionally relevant, as the selective blockade of Kv1.3 currents produced a significant decreased of VSMCs proliferation rate in all the preparations. These results point to Kv1.3 channels as good therapeutical targets to avoid unwanted VSMC remodelling. To explore the molecular mechanisms linking Kv1.3 expression to proliferation, we tried to reproduce the pro-proliferative effect of Kv1.3 heterologously expressed in HEK293 cells. Both cell counting and BrdU incorporation assays demonstrated that Kv1.3 over-expression promotes HEK cells proliferation, while Kv1.5 over-expression inhibits it. The use of Kv1.3 mutant channels in which either gating or permeation is affected indicate that the pro-proliferative effect of Kv1.3 is not dependent on its contribution to set resting membrane potential, but is abolished when voltage-dependent conformational changes are absent. These data suggest that Kv1.3 may be a moonlighting protein that regulates intracellular signalling pathways leading to cell proliferation by a mechanism that is independent of potassium flux.