Most and perhaps all natural‐cell‐mediated cytotoxicity (NCMC) may be activated by a response to exogenous infections. Specific‐pathogen‐free (SPF) mice have little or no natural killer (NK) cell activity, but when they are relocated in conventional conditions, they develop strong NCMC within 2 to 3 days. Unlike other SPF animals, hypothymic nude mice display good NCMC which is further augmented upon their entry into a pathogenic environment. The ontogeny, genetic control and other features of pathogen‐activated NCMC resemble those previously described for NK cells. An H2‐D region NCMC regulatory gene is active in either a homozygous or heterozygous state, but to be operative seems to require the presence of an additional complementing locus, which maps outside the H‐2 complex. It is proposed that H‐2 influences NCMC levels by affecting the expression or immunogenicity of NK cell‐activating determinants. Recently activated NK cells were non‐adherent and lacked la and Thy‐1 determinants. NCMC was not affected by treatment with monoclonal high‐titer Thy‐1.2 antisera and complement. However, an Ly‐6.2 antiserum did contain anti‐NK cytotoxic activity, which was shown by absorption analysis to be distinct from anti‐Ly‐6.2 activity. The NK antigen has a strain distribution pattern distinct from Ly‐5 and other Ly markers, but may be related or identical to NK‐1. Copyright © 1979 Wiley‐Liss, Inc., A Wiley Company