Natural killer (NK) cells perform immune surveillance for virally infected cells and tumor cells. The balance between the engagement of activating receptors, such as NKG2D, and inhibitory receptors on the NK cell surface determines whether the cells kill their targets. Through superresolution microscopy, Bálint et al. showed that NKG2D on the surface of unstimulated NK cells was organized into nanoclusters, which became differentially reorganized depending on whether the cells were exposed to MICA or ULBP2, two NKG2D ligands found on tumor cells. Stimulation with ULBP2, but not MICA, caused NKG2D to cluster with the receptor for the cytokine IL-15, which can also be presented on tumor cells, synergizing with NKG2D to enhance NK cell responses. These data suggest that NKG2D ligands have distinct outcomes on NK cell function, which may have relevance in the use of NK cells as an immunotherapy.