Natural killer (NK) cells express cell-surface receptors of the immunoglobulin and C-type lectin superfamilies that recognize major histocompatibility complex (MHC) class I peptides and inhibit NK-cell-mediated cytotoxicity(1). These inhibitory receptors possess ITIM sequences (for immunoreceptor tyrosine-based inhibitory motifs) in their cytoplasmic domains that recruit SH2-domain-containing protein tyrosine phosphatases, resulting in inactivation of NK cells(2-4). Certain isoforms of these NK-cell receptors lack ITIM sequences and it has been proposed that these ＇non-inhibitory＇ receptors may activate,rather than inhibit, NK cells(4-6). Here we show that DAP12, a disulphide-bonded homodimer containing an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain, non-covalently associates with membrane glycoproteins of the killer-cell inhibitory receptor (KIR) family without an ITIM in their cytoplasmic domain. Crosslinking of KIR-DAP12 complexes results in cellular activation, as demonstrated by tyrosine phosphorylation of cellular proteins and upregulation of early-activation antigens. Phosphorylated DAP12 peptides bind ZAP-70 and Syk protein tyrosine kinases, suggesting that the activation pathway is similar to that of the T- and B-cell antigen receptors.