Over the past five decades, natural killer (NK) cells have evolved from being a mysterious population of lymphocytes to central players in immune defense and regulation. Initially identified in the 1970s as "natural killer" cells capable of killing tumor and virus-infected cells without prior exposure, NK cells were distinguished from T cells by their lack of MHC restriction and their ability to recognize and eliminate cells lacking MHC class I molecules. This discovery laid the foundation for understanding NK cell biology and their role in host defense. The 1980s saw significant advances in characterizing NK cells, including the identification of their morphological features, functional subpopulations, and the discovery of key receptors such as CD16 and CD56. The 1990s brought the identification of inhibitory and activating NK receptors, including Ly49 and KIR in mice, and NKG2D in humans, which helped elucidate the mechanisms by which NK cells recognize and respond to infected or transformed cells. The 2000s marked the discovery of NK cell memory and licensing, revealing that NK cells can develop antigen-specific memory and respond to pathogens in a manner similar to T cells. This period also saw the development of technologies like mass cytometry, which revealed the remarkable diversity of NK cells in human peripheral blood. In the 2010s and beyond, NK cells have become a focus of clinical research, with efforts to engineer NK cells for cancer immunotherapy. Advances in CRISPR technology have enabled the genetic modification of NK cells for therapeutic use, and NK cell-based therapies are now being explored for their potential in treating various cancers and autoimmune diseases. This review highlights the major milestones in NK cell research over the past five decades, emphasizing their role in immune defense, their ability to recognize and eliminate infected or transformed cells, and their potential as therapeutic targets in clinical settings. The ongoing research continues to uncover new aspects of NK cell biology, offering promising avenues for future therapeutic applications.Over the past five decades, natural killer (NK) cells have evolved from being a mysterious population of lymphocytes to central players in immune defense and regulation. Initially identified in the 1970s as "natural killer" cells capable of killing tumor and virus-infected cells without prior exposure, NK cells were distinguished from T cells by their lack of MHC restriction and their ability to recognize and eliminate cells lacking MHC class I molecules. This discovery laid the foundation for understanding NK cell biology and their role in host defense. The 1980s saw significant advances in characterizing NK cells, including the identification of their morphological features, functional subpopulations, and the discovery of key receptors such as CD16 and CD56. The 1990s brought the identification of inhibitory and activating NK receptors, including Ly49 and KIR in mice, and NKG2D in humans, which helped elucidate the mechanisms by which NK cells recognize and respond to infected or transformed cells. The 2000s marked the discovery of NK cell memory and licensing, revealing that NK cells can develop antigen-specific memory and respond to pathogens in a manner similar to T cells. This period also saw the development of technologies like mass cytometry, which revealed the remarkable diversity of NK cells in human peripheral blood. In the 2010s and beyond, NK cells have become a focus of clinical research, with efforts to engineer NK cells for cancer immunotherapy. Advances in CRISPR technology have enabled the genetic modification of NK cells for therapeutic use, and NK cell-based therapies are now being explored for their potential in treating various cancers and autoimmune diseases. This review highlights the major milestones in NK cell research over the past five decades, emphasizing their role in immune defense, their ability to recognize and eliminate infected or transformed cells, and their potential as therapeutic targets in clinical settings. The ongoing research continues to uncover new aspects of NK cell biology, offering promising avenues for future therapeutic applications.