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-alpha-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 termed 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.