Dendritic cells (DC) are key players at the interface between innate resistance and cognate immunity. Recent evidence highlighted that innate effector cells can induce DC maturation, a checkpoint for the triggering of primary T cell responses in vivo. Moreover, mature DC also promote NK cell effector functions, necessary and sufficient, in some cases, for Th1 polarization. The site of the DC-NK cell interplay likely determines its relevance in physiopathology and the outcome on the ongoing immune response. This review focuses on the current knowledge of the regulation of NK cell priming by DC and, reciprocally, on the consequences of NK cell activation on DC functions. The relevance of DC-NK cell cross-talk in the control of infectious diseases and tumor growth is discussed, highlighting the impact of this dialogue on the design of immunotherapy protocols.