Recent studies have elucidated the functional links between natural killer (NK) cells and, demonstrating the reciprocal activation of these cell types through NK-DC interactions. The subsets of cells and molecular pathways involved in such interactions have been defined, and the possible anatomical sites of these interactions have also been reported. Murine experiments have demonstrated that injection of mature DCs induces rapid recruitment of NK cells to lymph nodes and that these NK cells provide interferon-gamma for Type 1 priming. Thus, there is an increasing body of in vivo evidence indicating that NK-DC interactions during the early phase of innate immunity can impact the quality and magnitude of the subsequent adaptive immune response. Importantly, these studies imply that NK cells might not serve merely as cytotoxic lymphocytes combating viral pathogens and malignant tumors, but must also be considered as important immunoregulatory cells with a significant influence on adaptive immunity. In contrast to the large volume of knowledge obtained through basic research, there is a relative paucity of information regarding NK cell function in adaptive immunity from clinical trials, as few DC vaccine studies have attempted to evaluate the nonspecific, yet potentially clinically relevant, NK response to immunization. In this article, the authors will review studies focusing on NK-DC interactions and highlight the most recent clinical findings relating to the potential role of NK cells in DC-based vaccine therapy.