Background <p>Natural killer cells (NKs) are critical effectors of innate immune surveillance, capable of eliminating target cells without prior antigen sensitization. The crucial role of NKs in cancer immunity has largely been highlighted in both hematological and solid tumors. Besides, NK-based cell therapies have gained momentum as a compelling alternative to T cell-based approaches, due to their off-the-shelf availability and lower risk of toxicity. Still, the intrinsic molecular mechanisms driving NK anti-tumor efficacy in different tumor contexts are poorly described, drastically impairing their clinical exploitation.</p> Aims <p>This review aims to provide a comprehensive overview of the transcriptional networks defining each step of NK anti-tumor response, from tissue recruitment to target recognition and cytotoxic activation. The molecular mechanisms triggering NK dysfunction in the tumor microenvironment are also highlighted from a transcriptional perspective. The described time- and context-dependent transcriptional machinery is characterized by a constant interplay between activators and repressors, which integrates and balances signals deriving from the surrounding tumor ecosystem.</p> Conclusions <p>Considering the relevance of transcription factors in controlling NK functions, their potential exploitation as novel therapeutic targets, through either pharmacological approaches or genome editing, is a new opportunity for cancer treatment.</p>