The BH3-only BID protein acts as a sentinel to interconnect specific death signals to the core apoptotic pathway. Our previous data demonstrated that BID is important for both S-phase arrest and cell death following DNA damage, and that the cell cycle arrest function is regulated by its phosphorylation by the ATM kinase. We also showed that a portion of cellular BID localizes to the nucleus. Here, we demonstrate that etoposide and ionizing radiation induce the exit of BID from the nucleus and that leptomycin B, a specific inhibitor of the nuclear export receptor CRM1, prevents the nuclear exit of BID. BID carries a nuclear export signal (NES) consensus motif; however, it does not seem to be functional. To examine the importance of BID nuclear export, we targeted BID to the nucleus by fusing it to a strong nuclear localization signal (NLS). NLS-BID is phosphorylated in a similar time course as wild-type BID, but does not exit the nucleus following etoposide treatment. Importantly, introducing NLS-BID into BID(-/-) cells failed to restore S-phase arrest and cell death in response to etoposide. These results implicate BID as a nuclear protein and raise the possibility that nucleocytoplasmic shuttling of BID is involved in regulating its activities in the DNA-damage response.