Natural killer (NK) cells can defend an organism against a variety of threats, probably using several different strategies to discriminate between normal and aberrant cells. According to the 'missing self' hypothesis, one function of NK cells is to recognize and eliminate cells that fail to express self major histocompatibility complex (MHC) class I molecules. In this article Hans-Gustaf Ljunggren and Klas Kärre review in vivo studies with H-2-deficient targets that support this hypothesis. In vitro studies, some of which have given conflicting results, are interpreted within a multiple choice model for NK cell recognition. The authors derive testable predictions for how MHC class I molecules act in cases where they control a rate-limiting step in the NK cell-target interaction.