Natural killer (NK) cells are effector lymphocytes of the innate immune system that play a crucial role in controlling tumors and microbial infections by limiting their spread and tissue damage. Recent research highlights their regulatory functions in interactions with dendritic cells, macrophages, T cells, and endothelial cells. NK cells can both limit and exacerbate immune responses, and their manipulation holds promise in improving hematopoietic and solid organ transplantation, promoting antitumor immunotherapy, and controlling inflammatory and autoimmune disorders. NK cells were initially described as large granular lymphocytes with natural cytotoxicity against tumor cells. They are now recognized as a distinct lineage of lymphocytes with both cytotoxic and cytokine-producing effector functions. The acquisition of cytotoxicity during evolution has been associated with sophisticated mechanisms that control cytolytic processes while avoiding tissue damage. Over the past fifteen years, significant progress has been made in understanding the mechanisms that allow NK cells to discriminate target cells from healthy 'self' cells, leading to the concept of a 'dynamic equilibrium' in NK cell activation. NK cells detect target cells through a variety of activating and inhibitory receptors, which regulate their activities. Activating receptors detect ligands on stressed cells, such as stress-induced self ligands (e.g., NKG2D ligands) and infectious nonself ligands (e.g., cytomegalovirus-encoded m157). Inhibitory receptors gauge the absence of constitutively expressed self molecules on target cells, such as MHC class I molecules. The integration of these antagonistic pathways governs the dynamic equilibrium that regulates NK cell activation. NK cells are widespread throughout lymphoid and nonlymphoid tissues, with distinct anatomical distributions and phenotypes. In humans, NK cells can be divided into CD56dim and CD56bright subsets, differing in their homing properties and functional characteristics. The role of NK cells in cancer, viruses, and other immune-related conditions is discussed, emphasizing their potential as therapeutic targets and their involvement in immune regulation. Despite their protective roles, NK cells can also act as mediators of innate immunopathology in certain conditions. Emerging aspects of NK cell biology, including their involvement in epithelial tissues and the control of major life-threatening infections, are also explored. Overall, NK cells not only participate in the control of various viruses and tumors but also act as regulatory cells during inflammation and influence adaptive immune responses.Natural killer (NK) cells are effector lymphocytes of the innate immune system that play a crucial role in controlling tumors and microbial infections by limiting their spread and tissue damage. Recent research highlights their regulatory functions in interactions with dendritic cells, macrophages, T cells, and endothelial cells. NK cells can both limit and exacerbate immune responses, and their manipulation holds promise in improving hematopoietic and solid organ transplantation, promoting antitumor immunotherapy, and controlling inflammatory and autoimmune disorders. NK cells were initially described as large granular lymphocytes with natural cytotoxicity against tumor cells. They are now recognized as a distinct lineage of lymphocytes with both cytotoxic and cytokine-producing effector functions. The acquisition of cytotoxicity during evolution has been associated with sophisticated mechanisms that control cytolytic processes while avoiding tissue damage. Over the past fifteen years, significant progress has been made in understanding the mechanisms that allow NK cells to discriminate target cells from healthy 'self' cells, leading to the concept of a 'dynamic equilibrium' in NK cell activation. NK cells detect target cells through a variety of activating and inhibitory receptors, which regulate their activities. Activating receptors detect ligands on stressed cells, such as stress-induced self ligands (e.g., NKG2D ligands) and infectious nonself ligands (e.g., cytomegalovirus-encoded m157). Inhibitory receptors gauge the absence of constitutively expressed self molecules on target cells, such as MHC class I molecules. The integration of these antagonistic pathways governs the dynamic equilibrium that regulates NK cell activation. NK cells are widespread throughout lymphoid and nonlymphoid tissues, with distinct anatomical distributions and phenotypes. In humans, NK cells can be divided into CD56dim and CD56bright subsets, differing in their homing properties and functional characteristics. The role of NK cells in cancer, viruses, and other immune-related conditions is discussed, emphasizing their potential as therapeutic targets and their involvement in immune regulation. Despite their protective roles, NK cells can also act as mediators of innate immunopathology in certain conditions. Emerging aspects of NK cell biology, including their involvement in epithelial tissues and the control of major life-threatening infections, are also explored. Overall, NK cells not only participate in the control of various viruses and tumors but also act as regulatory cells during inflammation and influence adaptive immune responses.