A major difficulty for tumor immunotherapy derives from the phenomenon that the encounter of the immune system with an antigen does not necessarily result in activation, but may also be followed by the induction of tolerance either by anergy or physical deletion. It is well established that the immune system becomes alerted only in the face of danger, i.e. upon ligand recognition in the context of increased expression of costimulatory molecules, adhesion molecules, and MHC molecules on antigen-presenting cells (APC). The pivotal role of CD4+ T lymphocytes in this process has been established. However, encounter of CD4+ T cells with either MHC class II- expressing melanoma cells or certain tumor antigen-presenting APC has been reported to induce antigen-specific tolerance. Thus, as more is learned about the molecular regulation of immune responses and the role of CD4+ T cells in particular, additional strategies to block inhibitory pathways of T-cell activation will be developed. Such strategies are likely to be based on a modulation of the context in which antigen is encountered by the immune system, e.g. in situ cytokine therapy, induction of costimulatory molecules or the simulation of 'danger' signals.