© 2014 Nabekura and Lanier. Natural killer (NK) cells provide important host defense against microbial pathogens and can generate a population of long-lived memory NK cells after infection or immunization. Here, we addressed whether NK cells can expand and differentiate after alloantigen stimulation, which may be important in hematopoietic stem cell and solid tissue transplantation. A subset of NK cell in C57BL/6 mice expresses the activating Ly49D receptor that is specific for H-2Dd. These Ly49D+NK cells can preferentially expand and differentiate when challenged with allogeneic H-2Ddcells in the context of an inflammatory environment. H-2Ddis also recognized by the inhibitory Ly49A receptor, which, when coexpressed on Ly49D+NK cells, suppresses the expansion of Ly49D+NK cells. Specificity of the secondary response of alloantigen-primed NK cells was defined by the expression of activating Ly49 receptors and regulated by the inhibitory receptors for MHC class I. Thus, the summation of signals through a repertoire of Ly49 receptors controls the adaptive immune features of NK cells responding to allogeneic cells.