We present data on the strain distribution and functional characteristics of the Ly-49 receptors A, C/I, D, and G2 on DX5+ natural killer (NK) cells. We have examined tyrosine phosphorylation of the Ly-49 molecules, regulation of NK cytotoxic functions, and in vivo marrow rejection capability. The flow cytometry results demonstrate a diverse and complex pattern of expression of the Ly-49 receptors in the 11 strains examined. The vast majority of NK cells express Ly-49s, although some NK1.1+ CD3+ cells also express these receptors. The results of our functional analysis indicate that H-2Dd was able to inhibit the function of Ly-49G2+ NK cells, not only in B6 mice, but also by NK cells derived from several haplotypes. The examination of Ly-49 receptor tyrosine phosphorylation, which is a biochemical measure of inhibitory function, was consistently observed in the 11 mouse strains examined. In contrast, analysis of Ly-49D function suggests its expression appears to be more restricted and that H-2Dd is an activating ligand for this receptor. In addition, the in vivo examination of both inhibitory (Ly-49G2) and activating (Ly-49D) receptors demonstrated regulatory roles of these class I binding receptors in marrow transplantation.