Natural killer (NK) cells are cytotoxic innate lymphocytes that protect against viral infection and tumor metastasis. Despite their inherent ability to kill a broad range of virally infected, stressed and transformed cells, low numbers of dysfunctional NK cells are often observed in many advanced solid human cancers. Here, we review the potential mechanisms that influence suboptimal mature NK cell recruitment and function in the tumor microenvironment (TME) of solid tumors. We further highlight current immunotherapy approaches aimed to circumvent NK cell dysfunction and discuss next-generation strategies to enhance adoptive NK cell therapy through targeting intrinsic and extrinsic checkpoints the regulate NK cell functionality in the TME. Understanding the mechanisms that drive NK cell dysfunction in the TME will lead to novel immunotherapeutic approaches in the fight against cancer.