NK cells kill and eliminate cancer cells, but in the tumor microenvironment they are often insufficiently active or inhibited by immunosuppressive ligands and cytokines. To overcome this, a number of strategies have been developed to enhance NK cell activity against cancer in these settings: (A) Chemo- and radiotherapy induce immunogenic cell death of cancers, leading to expression of NKG2D ligands, HMGB1, and other DAMPs that drive NK cell activation. (B) Surgery leads to the development of an immunosuppressive microenvironment, in part through the expansion of MDSCs and the release of inhibitory cytokines such as TGF-β. PDE5 inhibitors alongside viral vaccines have proven to be highly effective in reversing this dysfunction. (C) Oncolytic viruses (OVs) infect and lyse cancer cells, but can also infect DCs, leading to their maturation and driving DC-NK cross talk and subsequent NK activation. OVs can also be engineered to deliver cytokines and other immune stimulants to the microenvironment to activate the immune system. (D) Engineered cytokines such as ALT-803, an alternate form of IL-15, have increased potency compared with conventional cytokines. (E) Checkpoint blockers such as anti–PD-1/PD-L1 and anti-TIGIT relinquish NK cells from the immunosuppressive effects exerted by tumors, allowing them to perform their cytolytic functions. (F) NK cells from autologous or allogeneic sources can be safely used as adoptive cell therapy. (G) The use of CARs enhances the efficacy of adoptive therapy. In particular, CARs expressing NKG2D with the CD3ζ and DAP10 intracellular signaling motifs drive potent antitumor immune responses. (H) BiKEs and TriKEs bring NK cells spatially closer to their targets and activate them. The TriKE 161533 contains a CD16-targeting motif for NK cells, a CD33-targeting motif for cancer cells and MDSCs, and an IL-15 linker to activate NK cells.