NK therapies for CLL have a long history of development with only recent efforts showing promise. The first wave began in the late 1980s with the stimulation of peripheral blood mononuclear cells (PBMCs) using IL-2, IFNα, and/or anti-CD3 to produce lymphokine-activated killer cells (LAKs) [100,108,254,255,256,257]. While two studies found that the normal cytotoxic function of patient-derived cells could be restored [108,256], most demonstrated a persistent cytotoxic defect associated with CLL even after stimulation [100,254,255]. Furthermore, primary CLL leukemia cells are resistant to both patient-derived and healthy-donor-derived LAKs [100,254,255]. More recently, various cytokine protocols have been shown to effectively stimulate CLL patient NK cells in vitro, including IL-2, IL-15, IL-21, IL-12 + IL-15, and IL-2 + IL-18 [91,93,96,97,98,258]. These studies have shown the potential to revert patient NKs to normal or increased activity, although none have been used to expand the populations for use as an actual therapy, and some studies do show a persistent defect in NK activity [98]. The stimulation of allogeneic NK cells with an Epstein–Barr virus (EBV)-positive lymphoblastoid cell line (EBV-LCL) has been shown to induce anti-CLL cytotoxicity in vitro, particularly against poor-prognosis (p53 mutated, IGHV unmutated) patient samples [170,259,260,261]. CD19 or CD20 chimeric antigen receptor NK cells (CAR-NK) also show significant potential for CLL. This strategy was first demonstrated using the NK-92 cell line, which showed the CAR-dependent killing of CLL in vitro [262,263]. This was improved by using HLA-mismatched NKs expanded from cord blood and transduced with anti-CD19 CAR, IL-15, and an inducible caspase 9. These CAR-NKs show effective expansion, cytotoxic activity, and NK survival in vitro and in vivo [264]. Notably, however, these authors found that patient-derived CAR-NKs had inferior cytotoxic activity in vitro in comparison with cord blood-derived CAR-NKs [264]. This work was translated to a small phase 1–2 trial of 11 patients with non-Hodgkin lymphoma or CLL, which demonstrated the safety of the NK cell product without graft-versus-host disease (GVHD), cytokine release syndrome, or neurotoxicity (major concerns with CAR-T therapy) [252]. The main adverse events were cytopenias, which were likely related to the fludarabine/cyclophosphamide conditioning regimen, although the contribution of the NK cells could not be excluded [252]. Most (4/5) CLL patients in this study achieved objective responses, although it is difficult to distinguish the effects of the NK cell treatment from the conditioning regimen, and most patients quickly moved to subsequent treatment after receiving NKs [252]. Similarly, another group demonstrated the in vitro anti-CLL cytotoxicity of a CAR-NK expressing CD19 CAR, high-affinity non-cleavable CD16, and a membrane-bound IL-15/IL-15R fusion molecule [265]. Most recently, our lab tested the expansion of NK cells using membrane-bound IL-21 (mbIL-21) expressing feeder cells, demonstrating that this stimulation produces high numbers of NK cells with potent anti-CLL activity in vitro and in vivo, including both allogeneic and autologous targets [266]. The administration of a targeted antibody here is required.