The role of K+ channel activity during cell cycle progression has become a research topic of considerable interest. Blocking of K+ channels inhibits the proliferation of many cell types, although the mechanism of this inhibition is unclear. There is speculation that K+ channels differentially regulate the electrical potential of the plasma membrane (Vm) during proliferation. We have demonstrated that in tumor cells the value of Vm is clamped to rather depolarized values by K+ channels belonging to the HERG family. We report here that tumor cell lines preferentially express the hergl gene and a truncated, N-deleted form that corresponds to herg1b. This alternative transcript is also expressed in human primary acute myeloid leukemias. Both HERG1 and HERG1B proteins are expressed on the plasma membrane of tumor cells and can form heterotetramers. The expression of HERG protein isoforms is strongly cell cycle-dependent, accounting for variations in HERG currents along the mitotic cycle. Moreover, the blocking of HERG channels dramatically impairs cell growth of HERG-bearing tumor cells. These results suggest that modulated expression of different K+ channels is the molecular basis of a novel mechanism regulating neoplastic cell proliferation.