NK cells are innate immune lymphocytes that can react to cells lacking self-MHC class I. However, NK cells that cannot engage self-MHC through an inhibitory receptor are resistant to stimulation through their activation receptors. To become licensed (i.e., functionally competent to be triggered through its activation receptors), an NK cell must engage host MHC class I via a MHC class I-specific inhibitory receptor, such as a member of the murine Ly49 family. To explore potential determinants of NK cell licensing on a single Ly49 receptor, we have investigated the relative licensing impacts of the b, d, k, q, r, and s H2 haplotypes on Ly49A(+) NK cells. The results indicate that licensing is essentially analog but is saturated by moderate-binding MHC class I ligands. Interestingly, licensing exhibited a strong inverse correlation with a measure of cis engagement of Ly49A. Finally, licensing of Ly49A(+) NK cells was found to be less sensitive to MHC class I engagement than Ly49A-mediated effector inhibition, suggesting that licensing establishes a margin of safety against NK cell autoreactivity.