The article provides a comprehensive overview of the discovery and advancements in the understanding of natural killer (NK) cells over the past five decades. Initially described in 1973, NK cells were found to exhibit non-specific cytotoxic activity against tumor cells and pathogens without prior exposure, and their activity was distinct from MHC-restricted, antigen-specific T cells. Over the years, research has expanded the knowledge of NK cells from in vitro observations to their in vivo relevance in host defense and immune regulation. Key milestones include the discovery of NK cell-mediated cytotoxicity in mice and humans, the identification of inhibitory and activating receptors, and the establishment of the "missing-self" hypothesis. The role of NK cells in herpesvirus defense and the identification of molecular markers such as CD16 and CD57 have also been crucial. Recent advancements have focused on the diversity of NK cells, the development of NK cell-based therapies, and the exploration of their memory and licensing mechanisms. The article highlights the evolution of conceptual advancements, including the understanding of NK cells' regulatory functions and their role in autoimmune diseases. It also discusses the discovery of tissue-resident NK cells and the emergence of innate lymphoid cells (ILCs) as distinct lineages with functions similar to NK cells. Looking ahead, the author suggests that future research should address questions about NK cell memory, their role in autoimmune diseases, and strategies to enhance NK cell function in hostile tumor microenvironments. The clinical potential of NK cells, particularly in cancer therapy, is also discussed, along with the development of NK cell engagers for targeted therapies.The article provides a comprehensive overview of the discovery and advancements in the understanding of natural killer (NK) cells over the past five decades. Initially described in 1973, NK cells were found to exhibit non-specific cytotoxic activity against tumor cells and pathogens without prior exposure, and their activity was distinct from MHC-restricted, antigen-specific T cells. Over the years, research has expanded the knowledge of NK cells from in vitro observations to their in vivo relevance in host defense and immune regulation. Key milestones include the discovery of NK cell-mediated cytotoxicity in mice and humans, the identification of inhibitory and activating receptors, and the establishment of the "missing-self" hypothesis. The role of NK cells in herpesvirus defense and the identification of molecular markers such as CD16 and CD57 have also been crucial. Recent advancements have focused on the diversity of NK cells, the development of NK cell-based therapies, and the exploration of their memory and licensing mechanisms. The article highlights the evolution of conceptual advancements, including the understanding of NK cells' regulatory functions and their role in autoimmune diseases. It also discusses the discovery of tissue-resident NK cells and the emergence of innate lymphoid cells (ILCs) as distinct lineages with functions similar to NK cells. Looking ahead, the author suggests that future research should address questions about NK cell memory, their role in autoimmune diseases, and strategies to enhance NK cell function in hostile tumor microenvironments. The clinical potential of NK cells, particularly in cancer therapy, is also discussed, along with the development of NK cell engagers for targeted therapies.