Therapies targeting the immune system are revolutionising cancer treatment by reactivating tumor-resident cytotoxic lymphocytes. Current clinical practice and drug development is focused on checkpoints known to suppress tumor-resident CD8 T cells, however given the emerging resistance to such therapies and the unresponsiveness of the majority of cancer patients, interest in other effector populations, such as natural killer (NK) cells is growing. NK cells possess an innate ability to detect and lyse transformed cells and NK cell activity is inversely correlated to cancer incidence in humans and experimental metastasis in mice. In the context of NK cell immune surveillance, it is not clear why some solid tumours generate metastasis while others do not. Our recent generation of the specific NK cell deficient mouse has revealed that several primary tumours models regarded as non-metastatic do indeed generate spontaneous metastasis that are specifically detected and eradicated by NK cells. Furthermore, increasing the activity of NK cellsin vivo by deletion of NK cell checkpoints identified by our team dramatically reduces tumour burden in highly metastatic cancer models. Genome-wide CRISPR screens using NK cell dependent mouse tumour models have revealed novel pathways to increase NK cell immunosurveillance and pathways of tumour immune-evasion. These pathways are being validated in patient-derived NK cells using a gene-editing approach optimized for primary human lymphocytes.