Natural killer (NK) cells and cytotoxic T (CD8) cells are two of the most important types of immune cells in our body, protecting it from deadly invaders. While the NK cell is part of the innate immune system, the CD8 cell is one of the major components of adaptive immunity. Still, these two very different types of cells share the most important function of destroying pathogen-infected and tumorous cells by releasing cytotoxic granules that promote proteolytic cleavage of harmful cells, leading to apoptosis. In this review, we look not only at NK and CD8 T cells but also pay particular attention to their different subpopulations, the immune defenders that include the CD56CD16, CD56CD16, CD57, and CD57CD16 NK cells, the NKT, CD57CD8, and KIRCD8 T cells, and ILCs. We examine all these cells in relation to their role in the protection of the body against different microorganisms and cancer, with an emphasis on their mechanisms and their clinical importance. Overall, close collaboration between NK cells and CD8 T cells may play an important role in immune function and disease pathogenesis. The knowledge of how these immune cells interact in defending the body against pathogens and cancers may help us find ways to optimize their defensive and healing capabilities with methods that can be clinically applied.