The possible role of the immune system in resisting human malignancies has long been debated. Several recent findings from animal and human studies have restimulated interest in the immune surveillance hypothesis for tumor control. These findings have been complied from various disciplines including cytokine therapy, adoptive immunotherapy, and gene therapy. Following the initial euphoria, it is now clear that immunotherapy of selected cancer cases in the early stages of tumor development may make an important contribution to tumor control, particularly in dealing with minimal residual disease after tumor debulking. This review discusses some of these issues and proposes approaches that could pave the way for better selection of the patients best suited for immunotherapy. We would argue that therapies directed at the re-expression of major histocompatibility complex (MHC) class I antigens might improve outcomes in immune-therapy-based treatments.