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Natural Killer (NK) cells are effector lymphocytes with the ability to generate an antitumor response. NK cells encompass a diverse group of subsets with different properties and have the capacity to kill cancer cells by different means. However, tumor cells have developed several mechanisms to evade NK cell-mediated killing. In this chapter, we summarize some aspects of NK cell biology with the aim to understand the competence of these cells and explore some of the challenges that NK cells have to face in different malignancies. Moreover, we will review the current knowledge about the role of NK cells in tumor progression and describe their phenotype and effector functions in tumor tissues and peripheral blood from cancer patients. Finally, we will recapitulate several findings from different studies focused on determining the prognostic value of NK cells in distinct cancers., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)