The human ether-a-go-go related gene (HERG) potassium channel has elicited intense scientific interest due to its role in cardiac repolarization and its association with arrhythmia and sudden cardiac death. Increasing evidence indicates the involvement of HERG channels in the pathophysiology of cancer. In the present study we investigated the expression of HERG protein in MDA-MB-435S melanoma cells, and its importance in regulating cell proliferation and migration. Our results showed that HERG was expressed on protein and mRNA levels in MDA-MB-435S melanoma cells. In these cells blockade of HERG channels with the HERG blockers E 4301 or cisapride attenuated both proliferation and migration of the cells. Activation of HERG with PD118057 stimulated cell migration. Furthermore, HERG small interfering (si) RNA attenuated the proliferation and migration of the cells. Incubation of MDA-MB-435S cells with E 4301 decreased the phosphorylation of mitogen-activated protein (MAP) kinase and the expression of the c-fos transcription factor. In control experiments, overexpression of HERG channels in HEK-293 cells dramatically increased the proliferation and migration of the cells and blocking HERG in these cells attenuated both proliferation and migration. Our results indicate that MDA-MB-435S cells express HERG channels and blockade of HERG results in the attenuation of both proliferation and migration by a mechanism dependent, at least in part, on an inhibition of the MAP kinase/c-fos pathway.