Multiple myeloma (MM) is an essentially incurable malignancy associated with profound immune dysregulation. Despite the advent of novel therapies and improvements in survival over the last 10 years, death from progressive disease and infection remains a common outcome. Natural killer (NK) cells are CD56(+)CD3(-) large granular lymphocytes that constitute a key cellular subset of the innate immune system. For over 30 years, the relationship between NK cells and MM has been described in the clinical setting and characterized in the laboratory. Data suggest that NK cells may play a role in the immune response to MM; however, this effect is lost due to immunoevasive strategies utilized by MM. Nevertheless, progress in the understanding of the mechanisms perpetuating this effect have led to new opportunities to recover or augment NK cell function therapeutically in MM. In fact, the novel agents thalidomide, lenalidomide and bortezomib all confer anti-MM effects, in part, through enhancement of NK cell function. Currently, the development of therapies designed specifically to increase NK cell cytotoxicity against MM is under way. The present review summarizes the current understanding of the NK cell versus MM effect and characterizes therapeutic interventions that exert anti-MM efficacy via NK cell function against the disease.