A major challenge in cancer immunotherapy is the identification of effective strategies for enhancing its clinical efficacy. One approach is based on adjuvants capable of breaking tolerance against tumor-associated antigens. Interferon-alpha(IFN-alpha), an antiviral cytokine with a long record of clinical use, has recently been shown to act as an effective adjuvant in cancer patients. Notably, a special interest is currently focused on the use of dendritic cells (DC) generated in the presence of IFN-alpha (IFN-DC) for the preparation of anticancer vaccines. An additional approach for enhancing the response to immunotherapy relies on its combination with chemotherapy. In fact, an ensemble of results from both studies in animal models and pilot clinical trials suggest that certain chemotherapeutic agents can act, under defined conditions, as strong adjuvants for enhancing the efficacy of immunotherapy. These results open new opportunities for designing mechanism-based combination therapies involving both chemotherapy and new-generation cancer vaccines, including IFN-DC-based vaccines.