Simple SummaryThe voltage-dependent potassium channel Kv1.3 is a potential target for cancer therapies. This channel exhibits a complex repertoire of physiological functions such as proliferation, activation, insulin sensitivity, nerve action potential and apoptosis among others. Furthermore, the expression and activity of Kv1.3 remodels in various types of tumors. Kv1.3 forms heteroligomeric complexes by association with a number of ancillary proteins that fine-tune the function of the complex. In addition, protein kinase signaling networks are essential for comprehending tumorigenesis. Kv1.3, but also its partners, undergoes phosphorylation-dephosphorylation cycles shaping and remodeling the biology of the channelosome. Therefore, this review compiles protein kinase mechanisms on Kv1.3 to understand regulatory mechanisms during tumor development.AbstractThe voltage-gated potassium channel Kv1.3 plays a pivotal role in a myriad of biological processes, including cell proliferation, differentiation, and apoptosis. Kv1.3 undergoes fine-tuned regulation, and its altered expression or function correlates with tumorigenesis and cancer progression. Moreover, posttranslational modifications (PTMs), such as phosphorylation, have evolved as rapid switch-like moieties that tightly modulate channel activity. In addition, kinases are promising targets in anticancer therapies. The diverse serine/threonine and tyrosine kinases function on Kv1.3 and the effects of its phosphorylation vary depending on multiple factors. For instance, Kv1.3 regulatory subunits (KCNE4 and Kvβ) can be phosphorylated, increasing the complexity of channel modulation. Scaffold proteins allow the Kv1.3 channelosome and kinase to form protein complexes, thereby favoring the attachment of phosphate groups. This review compiles the network triggers and signaling pathways that culminate in Kv1.3 phosphorylation. Alterations to Kv1.3 expression and its phosphorylation are detailed, emphasizing the importance of this channel as an anticancer target. Overall, further research on Kv1.3 kinase-dependent effects should be addressed to develop effective antineoplastic drugs while minimizing side effects. This promising field encourages basic cancer research while inspiring new therapy development.