The IFN-α family are pleiotropic cytokines with the longest record of clinical use. Over the last decade, new biological effects of IFN-α on immune cells, including dendritic cells, have been described, supporting the concept that these cytokines can act as effective vaccine adjuvants. Recently, an important advance in our understanding of the mechanisms of interferon adjuvant activity has been achieved. Some clinical studies have been performed to assess the adjuvant activity in individuals immunized with preventive vaccines, showing variable results depending on interferon/vaccine formulation and vaccinated subjects. In spite of many data in animal models, little information is available on the possible advantage of utilizing IFN-α as an adjuvant for cancer vaccines in humans. Further clinical trials specifically designed to explore vaccine adjuvant activity are needed in order to define the best conditions for using IFN-α or IFN-α-conditioned dendritic cells for the development of therapeutic vaccines.