Techniques for modulating immune cells for cancer therapy have been widely studied. One key approach that is being clinically tested is developing tumor-destructive cell-mediated immune responses by regulating co-stimulatory molecules. 4-1BB (CD137), a member of the TNF receptor family, is expressed following activation of T and NK cells. Recently, it has been reported that DCs also express 4-1BB. Crosslinking of 4-1BB provides a potent co-stimulatory signal for lymphocytes via signal transduction pathways that modulate a number of cellular responses. One remarkable response is stimulation of anti-tumor activity in vivo and in vitro. We here review the potential role of 4-1BB in cancer immunotherapy focusing on the cellular and molecular mechanisms involved.