The Ly-49A molecule is an NK cell receptor specific for MHC class I molecules on target cells. When Ly-49A engages H-2Dd, Ly-49A+ NK cells become globally incapable of killing their targets in vitro. This interaction also occurs in vivo. Ly-49A belongs to a family of highly related molecules, including Ly-49C (5E6 antigen) and LGL-1 that also determine NK cell specificity. In the NK gene complex, the Ly-49 family is genetically linked to genes encoding NKR-P1 and CD69 that are structurally related and capable of activating NK cells. Finally, Ly-49 may be related to human molecules that are selectively expressed on NK cells and influence NK cell specificity. These findings highlight the emerging significance of the Ly-49 family in NK cell activity.