Combination immunotherapy approaches involving radiation, chemotherapy, androgen manipulation and T-cell modulation have been studied extensively in animal models, setting the stage for clinical trials. Radiation therapy, in particular, is an interesting modality in this regard, leading to synergistic efficacy when used in combination with immunotherapies in several models. Chemotherapy, the foundation of treatment of metastatic disease, may also augment the immune response to cancer; however, the potential immunosuppressive effects of chemotherapy render issues of dosing and timing critical. Perhaps, the most exciting combinatorial approach may be the co-administration of multiple immunological treatments. For example, in preclinical investigations, combined blockade of programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which have key roles in the negative regulation of T-cell activation, has been shown to enhance antitumour immune responses compared with either agent alone. Taken together, the available data provide a strong rationale for initiating combination clinical trials, but lend a note of caution in that issues of dosing and timing likely require careful exploration in a phase II setting.