Natural Killer (NK) cell dysfunction has been observed in multiple chronic conditions such as infectious diseases, cancer, or inflammatory disorders. In cancer, NK cell dysfunction is often aggravated upon tumor growth or dissemination and is more pronounced in tumor-infiltrating NK cells than in circulating ones. NK cell dysfunction is however highly heterogeneous depending on the condition or tumor characteristics, and this heterogeneity is likely due to different molecular pathways engaged. In particular, chronic engagement of activating receptors can lead to NK cell exhaustion, and multiple regulatory cells and molecules may suppress NK cell function, which could combine with exhausting signals. NK cell maturation is also often impaired during chronic conditions, and NK cells can also be reprogrammed to less cytotoxic subsets or even regulatory ones, under the influence of cytokines or following contact with tumor cells. This chapter highlights the changes in NK cell phenotype and function observed in different chronic conditions, underlines some well-established pathways, and raises some important questions that remain to be addressed in the field of NK cell exhaustion.