Transient Receptor Potential (TRP) channels modulate intracellular Ca2+ concentrations, controlling critical cytosolic and nuclear events that are involved in the initiation and progression of cancer. It is not, therefore, surprising that the expression of some TRP channels is altered during tumor growth and metastasis which are strictly dependent on tumor vascularization.On the other hand, although the expression and role of ion channels and transporters in the vascular endothelium is well recognized and subject of recent reviews, only recently TRP channels involvement in tumor vascularization have been recognized.In the last years we investigated in detail the Ca2+ machinery and TRP channels roles in Tumor derived endothelial cells (TEC) compared with normal endothelial cells (EC) and evaluated the differential involvement of key-intracellular messengers triggered by proangiogenic factors (VEGF, bFGF) in vascular ECs, such as AA, nitric oxide (NO) and hydrogen sulfide (H2S). We correlated cell migration, proliferation and tubulogenesis in vitro to intracellular Ca2+ signaling 1-3.Our data suggest that TRPV4 is likely to be a key player in tumor vascularization and in particular tumor-derived endothelial cell (TEC) migration induced by arachidonic acid (AA), which endogenously activate the channel. TEC display a significant increase in TRPV4 expression, which is correlated with greater Ca2+ entry. Wound healing assays revealed a key role of TRPV4 in regulating cell migration of TEC but not “normal” EC (HMVEC). Knockdown of TRPV4 expression completely abolished AA-induced TEC migration, suggesting that TRPV4 mediates the pro-angiogenic effects promoted by AA. Furthermore, pre-incubation of TEC with AA induced actin remodeling and a subsequent increase in the surface expression of TRPV4. This was consistent with the increased plasma membrane localization of TRPV4 and higher AA-stimulated Ca2+ entry in the migrating cell 4.On the other hand recent advancement in the characterization of the TRPM8 differential expression in normal versus TEC and its role in cell migration inhibition suggest that the balance between TRPV4 and TRPM8 could be critical to control such mechanism.The possible implication of this balancing in tumor vascularization and the cellular and molecular mechanisms implicated will be discussed.