Expressed predominantly on myeloid and natural killer (NK) cells, DAP12 is an adapter protein that can associate with a variety of receptors. To date, DAP12 has predominantly been characterized as an adapter protein that activates various myeloid and NK cell effector functions; however, recent findings have demonstrated that DAP12 can also inhibit myeloid functions. Here we review the dual functionality of DAP12 and present evidence that DAP12 can suppress as well as activate NK cells.