Interferons (IFNs) are critical components of the host immune system, serving as antiviral agents, immunomodulators and inhibitors of cell growth. Among peripheral blood mononuclear cells, the primary IFN-α-producing cell is a light density, HLA-DR⁺ cell negative for cell surface markers typical for T cells, B cells, monocytes, natural-killer or progenitor cells and has been tentatively the ‘natural’ IFN-producing cell' or NIPC. Although present in very low frequency (approximately 1:1000 among peripheral blood mononuclear cells), the NIPC are very potent, with an individual cell able to produce 1–2 IU of IFN. In this review, the characteristics, phenotype, regulation and relationship of NIPC to human disease are discussed.