The article reviews the structural and biochemical properties of activating and inhibitory receptors on natural killer (NK) cells, focusing on ITAM-dependent activating receptors, NKG2D-DAP10 receptor complexes, and the CD244 receptor system. NK cells, which patrol for transformed or pathogen-infected cells, have a repertoire of inhibitory receptors that regulate their activation. These receptors, such as killer cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptors (LILRs), share a common signaling motif, the immunoreceptor tyrosine-based inhibitory motif (ITIM). When engaged, ITIM-bearing receptors recruit phosphatases like SHP-1 or SHP-2, which dephosphorylate substrates linked to activating receptors, terminating NK cell responses. In contrast, activating NK receptors, such as those bearing ITAMs, form complexes with DAP12, FcεRI-γ, or CD3-ζ subunits, and signal through a pathway similar to that of B and T cells. Engagement of these receptors leads to phosphorylation of ITAMs by Src family kinases, followed by binding to Syk and ZAP-70. The downstream signaling cascade involves actin cytoskeleton reorganization, leading to cytotoxic granule release and cytokine production. The NKG2D-DAP10 receptor complex, a type II transmembrane glycoprotein, associates with DAP10 or DAP12 and recruits Grb2 and p85, leading to Ca2+ influx and cytotoxicity. CD244, a member of the SLAM family, can form activating or inhibitory complexes with SAP, EAT-2, or ERT adaptors, depending on the context. The activating function of CD244 is abrogated in patients with X-linked lymphoproliferative disease, while its inhibitory function is predominant in mouse NK cells. The dynamic interactions between inhibitory and activating receptors regulate NK cell responses, and future studies will focus on understanding these interactions in health and disease.The article reviews the structural and biochemical properties of activating and inhibitory receptors on natural killer (NK) cells, focusing on ITAM-dependent activating receptors, NKG2D-DAP10 receptor complexes, and the CD244 receptor system. NK cells, which patrol for transformed or pathogen-infected cells, have a repertoire of inhibitory receptors that regulate their activation. These receptors, such as killer cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptors (LILRs), share a common signaling motif, the immunoreceptor tyrosine-based inhibitory motif (ITIM). When engaged, ITIM-bearing receptors recruit phosphatases like SHP-1 or SHP-2, which dephosphorylate substrates linked to activating receptors, terminating NK cell responses. In contrast, activating NK receptors, such as those bearing ITAMs, form complexes with DAP12, FcεRI-γ, or CD3-ζ subunits, and signal through a pathway similar to that of B and T cells. Engagement of these receptors leads to phosphorylation of ITAMs by Src family kinases, followed by binding to Syk and ZAP-70. The downstream signaling cascade involves actin cytoskeleton reorganization, leading to cytotoxic granule release and cytokine production. The NKG2D-DAP10 receptor complex, a type II transmembrane glycoprotein, associates with DAP10 or DAP12 and recruits Grb2 and p85, leading to Ca2+ influx and cytotoxicity. CD244, a member of the SLAM family, can form activating or inhibitory complexes with SAP, EAT-2, or ERT adaptors, depending on the context. The activating function of CD244 is abrogated in patients with X-linked lymphoproliferative disease, while its inhibitory function is predominant in mouse NK cells. The dynamic interactions between inhibitory and activating receptors regulate NK cell responses, and future studies will focus on understanding these interactions in health and disease.