The best-known function of the ether-a-go-go related gene (HERG) is the repolarization of the cardiac action potential in mediating the IKr current. Increasing evidence indicates that HERG channels are also involved in the proliferation of cancer cells. Small-cell lung cancer (SCLC) is an aggressive form of cancer, with median survival time from diagnosis of only months. Using the patch clamp technique, HERG K+ currents were recorded in five SCLC cell lines (H69,H82, OH1, OH3 and SW2). The erg current could be blocked with E-4031, a specific blocker of erg K+ channels, and increased by the erg channel activator NS1643. Using RT-PCR transcripts for HERG1a, HERG1b, HERG2 and HERG3 were detected in all five SCLC cell lines. We then found that blocking of the erg current by addition of E-4031 (1 + 5mM) or increasing the erg current amplitude by addition of the erg activator NS1643 (10 + 30mM) to the culture medium had no effect on SW2 cell proliferation. In contrast, reducing HERG1 channel expression by using siRNA technology, SW2 cell proliferation decreased by 61% as compared to the untreated group. The inhibition of HERG1 channel protein expression was confirmed by Western blot. Accordingly, whole-cell patch clamp recordings from cells transfected with siRNA showed that in these cells the erg current was decreased. Our results indicate that erg channels may have a conducting function and a non-conducting function. As yet, we do not know, which part of the HERG channel protein is responsible for this non-conducting function which leads to a decrease in cell proliferation. Whether HERG channels can be considered as novel targets for anti-cancer therapies remains to be shown.