Dendritic cells (DCs) and natural killer (NK) cells play a critical role in early defences against cancer and infections. They specialise in complementary functions, including IL-12 or IFN-α/β secretion and antigen presentation for the former, and IFN-γ secretion and killing of infected or tumour cells for the latter. Both DCs and NK cells are also sensors of the immune system that have developed different, but partially overlapping, systems to identify pathology associated danger signals. Evidence of NK–DC interaction has accumulated recently. This interaction may lead to NK cell activation, DC activation, or apoptosis depending on the activation status of both cell types. Thus, the outcome of NK–DC crosstalk is likely to influence both innate and adaptive immune responses. This review addresses the molecular mechanisms under-lying the different NK–DC interactions, and their in vivo significance in anti-tumour or antimicrobial immunity. Finally, we discuss the potential clinical implications of this new field.