The crucial role of voltage-gated channels in the pathophysiology of cancer has become a generally accepted concept. The molecular nature of this implication is however obscure, and appears to be specific for each channel. KV10.1 is a brain-specific voltage-gated potassium channel ectopically expressed in a majority of extra-cranial solid tumors and a significant fraction of acute myeloid leukemia. Expression of KV10.1 is tightly controlled by E2F1, p53 and miR34a; alterations on any of these factors lead to aberrant expression of the channel. Once expressed, KV10.1 confers a selective advantage to the cells, at least partly mediated by increased angiogenesis (through higher HIF1 activity and VEGF secretion), but it also directly modifies cell cycle through at least two independent mechanisms, direct activation of cyclin-dependent kinases and altered coordination of ciliogenesis. Its specificity for tumor tissue makes KV10.1 an attractive target for tumor management. Channel expression correlates with bad prognosis in several tumor types, and pharmacological or genetic inhibition of KV10.1 is able to reduce tumor progression. Channel inhibition alone does not induce regression in immunocompromised mice, possibly because the role of KV10.1 in tumor cells is partly independent of ion permeation. Immuno-targeted tools taking advantage of the tumor specificity of channel expression (a single-chain antibody against KV10.1 fused to the human soluble TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis in KV10.1 positive cancer cells, but not in non-tumor or KV10.1-negative tumor cells; in vivo, this resulted in efficacious tumor reduction in combination with doxorubicin.