Interferon-α (IFN-α) has proven to be a clinically effective antiviral and antineoplastic therapeutic drug for more than 16 years. During this time, evidence from in vitro laboratory studies and the clinical arena has supported the concept that IFN-α is an immunotherapeutic drug. By regulating a diverse set of cytokines and their receptors, IFN-α is uniquely positioned to prime the host immune response and provide an effective antineoplastic- and antiviral-immune response. IFN-α stimulates the innate cell-mediated response and then participates in the transition of the initial host innate response into an effective adaptive-immune response. IFN-α also drives the adaptive cell-mediated CD8+ T-cell response and helps to maintain a CD4+ Th1-cell population balance for an effective antineoplastic and antiviral host defense. This review will describe the current state of knowledge of IFN-α as an immunoregulatory protein and address specific issues of IFN-α as an immunotherapeutic for antineoplastic and antiviral diseases.