Natural killer (NK) cells are innate immune effector cells that control tumors and infections by limiting their spread. Recent research shows NK cells also regulate immune responses through interactions with dendritic cells, macrophages, T cells, and endothelial cells. Although NK cells may appear redundant in some immune conditions, their manipulation holds promise for improving transplantation, antitumor immunotherapy, and controlling inflammation and autoimmune disorders. NK cells were originally identified as large granular lymphocytes with natural cytotoxicity against tumor cells. They are now recognized as a distinct lineage with both cytotoxic and cytokine-producing functions. NK cells use activating and inhibitory receptors to detect target cells, with activating receptors recognizing stress-induced ligands and inhibitory receptors recognizing self-MHC class I molecules. This dynamic equilibrium regulates NK cell activation and determines whether they kill target cells. Activating receptors detect stress-induced ligands, such as NKG2D ligands, while other alert molecules include infectious nonself ligands and TLR ligands. NK cells express several TLRs, and exposure to TLR ligands induces IFN-γ production and enhances cytotoxicity. Inhibitory receptors, such as KIRs and CD94-NKG2A, recognize self-MHC class I molecules and provide tolerance to self while allowing toxicity toward stressed cells. Other inhibitory receptors recognize non-MHC self molecules and regulate NK cell activation. NK cells are widely distributed in lymphoid and nonlymphoid tissues, with a minor fraction of total lymphocytes in most tissues. In humans, NK cells are divided into CD56dim and CD56bright subsets, with CD56dim NK cells being cytotoxic and CD56bright NK cells producing cytokines. In mice, three NK cell subsets differ in CD11b and CD27 expression, with distinct tissue distributions. NK cells regulate immune responses through various mechanisms, including controlling microbial infections, tumor immunosurveillance, and viral infections. They can enhance or suppress immune responses depending on the context. NK cells also play a role in regulating adaptive immune responses by influencing dendritic cells, T cells, B cells, and endothelial cells. In cancer, NK cells can recognize and kill tumor cells, and their activity is associated with cancer risk. In viral infections, NK cells control viral replication and help in immune responses. NK cells can also contribute to immunopathology, such as in autoimmune diseases and inflammatory conditions. NK cells are involved in various physiological processes, including reproduction, where they support placental development. They also play a role in parasitic infections and HIV, with NK cell function being affected in these conditions. Overall, NK cells are essential for immune defense and have diverse functions in health and disease. Their role in immune regulation and disease control is increasingly recognized, highlighting their importance in both innate and adaptive immunity.Natural killer (NK) cells are innate immune effector cells that control tumors and infections by limiting their spread. Recent research shows NK cells also regulate immune responses through interactions with dendritic cells, macrophages, T cells, and endothelial cells. Although NK cells may appear redundant in some immune conditions, their manipulation holds promise for improving transplantation, antitumor immunotherapy, and controlling inflammation and autoimmune disorders. NK cells were originally identified as large granular lymphocytes with natural cytotoxicity against tumor cells. They are now recognized as a distinct lineage with both cytotoxic and cytokine-producing functions. NK cells use activating and inhibitory receptors to detect target cells, with activating receptors recognizing stress-induced ligands and inhibitory receptors recognizing self-MHC class I molecules. This dynamic equilibrium regulates NK cell activation and determines whether they kill target cells. Activating receptors detect stress-induced ligands, such as NKG2D ligands, while other alert molecules include infectious nonself ligands and TLR ligands. NK cells express several TLRs, and exposure to TLR ligands induces IFN-γ production and enhances cytotoxicity. Inhibitory receptors, such as KIRs and CD94-NKG2A, recognize self-MHC class I molecules and provide tolerance to self while allowing toxicity toward stressed cells. Other inhibitory receptors recognize non-MHC self molecules and regulate NK cell activation. NK cells are widely distributed in lymphoid and nonlymphoid tissues, with a minor fraction of total lymphocytes in most tissues. In humans, NK cells are divided into CD56dim and CD56bright subsets, with CD56dim NK cells being cytotoxic and CD56bright NK cells producing cytokines. In mice, three NK cell subsets differ in CD11b and CD27 expression, with distinct tissue distributions. NK cells regulate immune responses through various mechanisms, including controlling microbial infections, tumor immunosurveillance, and viral infections. They can enhance or suppress immune responses depending on the context. NK cells also play a role in regulating adaptive immune responses by influencing dendritic cells, T cells, B cells, and endothelial cells. In cancer, NK cells can recognize and kill tumor cells, and their activity is associated with cancer risk. In viral infections, NK cells control viral replication and help in immune responses. NK cells can also contribute to immunopathology, such as in autoimmune diseases and inflammatory conditions. NK cells are involved in various physiological processes, including reproduction, where they support placental development. They also play a role in parasitic infections and HIV, with NK cell function being affected in these conditions. Overall, NK cells are essential for immune defense and have diverse functions in health and disease. Their role in immune regulation and disease control is increasingly recognized, highlighting their importance in both innate and adaptive immunity.