Interferon production can be stimulated by a great variety of microbial and nonmicrobial agents other than viruses. The nonmicrobial inducers can be divided into polyanions, mitogens, and a miscellaneous category including the various endotoxins and antibiotics. The polyanions appear to require a stable, high molecular weight backbone and a high density of free anionic groups whether they are polynucleotides, plastics, or polysaccharides. Mitogen-induced interferon appears to be but one of a constellation of substances produced following lymphocyte transformation. The process of transformation can be stimulated either by specific immune recognition or non-specifically by phytohemagglutinin. Synthetic polynucleotide inducers are active; the thermostable, double-stranded RNA's are much more active than the double-stranded DNA's or 1-, 3-, or 4-stranded RNA's. Some success has been obtained with potentiation of nucleotide inducers through the use of polycationic substances, complexing with a polysaccharide, concurrent administration of a metabolic antagonist, or substitution of phosphate by thiophosphate in the polynucleotide backbone. The stages in the interaction of interferon stimulating RNA and cells can be divided into three steps: first, binding to cell surface, next, a temperature dependent "recognition" step, and finally, degradation and utilization of monomers in cellular RNA synthesis; the critical recognition site has not yet been determined. The vast majority of cell-associated polynucleotide remains at the surface of the cell. Information from animal models resembling human diseases suggests that certain of these nucleotide inducers may have clinical usefulness in therapy or prophylaxis.