It is now well accepted that type 1 interferons (IFNs), IFN-alpha and IFN-beta, in addition to being molecules with powerful antiviral activity, play a critical role in modulating immune responses to foreign and self-antigens. This review of the literature documents the immunomodulatory effects of IFN-alpha and discusses its position and importance in the cytokine cascade. In addition, this review attempts to organize the literature describing local and systemic immunomodulatory effects of orally administered low doses of IFN-alpha, and provide a physiological explanation for the mechanism of action. Evidence suggests that, early in the process of antigen presentation to T helper (Th) cells, IFN-alpha derived principally from the antigen-presenting cells (APC) provides an important signal for Th precursor differentiation in favor of a Th1 immune response. IFN-alpha, perhaps via upregulation of the high-affinity interleukin-12 beta 1/beta 2 (IL-12 beta 1/beta 2) receptor, renders Th1 cells responsive to IL-12 resulting in production of high levels of IFN-gamma crucial to the development of Th1 immune responses. In addition to being instrumental in the development of Th1 immune responses, IFN-alpha appears to be the major cytokine responsible for the amplification of the CD8(+) T cell response and resistance to viral infections. Orally administered IFN-alpha induces similar Th1 cytokine responses in buccal mucosal lymph nodes (LN), including upregulation of IFN-gamma expression and downregulation of IL-4. Moreover, reports of systemic immune effects such as decreased autoimmune responses, increased antiviral and antibacterial responses, and generalized immune function changes after oral IFN-alpha administration are consistent with the known immunomodulatory role of IFN-alpha in a physiological setting. Responses to orally administered low doses of IFN-alpha also adhere to the principle of low-dose priming and high-dose anergy that dictates the cellular and cytokine responses to exogenously added cytokines both in vivo and in vitro. These observations collectively suggest that IFN-alpha administered to mucosal-associated immune tissue replicates the known physiological role of IFN-alpha, including regulation of CD4(+) Th1 immunomodulatory cells and activation of CD8(+) effector cells, which are both crucial to development of protective immune responses. What remains to be determined is how local mucosal immune responses to IFN-alpha given orally are translated into systemic immune responses and resistance to disease. This important question, the answer to which will have profound implications for new immunotherapies for immune-based diseases, is the focus of current research.