Background. NK cells are able to kill tumor and virus-infected cells without the need of prior antigen stimulation. The killing of these target cells is regulated by inhibitory, lysis and co-stimulatory receptors that are expressed on the surface of NK cells. Principal Findings. CD100 (Semaphorin 4D), a 150kD transmembrane protein, is expressed on the surface of activated NK cells as a homodimer, mediates the killing of target cells by binding to CD72. CD100 is not involved directly in the killing process but is rather increases NK cytotoxicity by enhancing the adhesion between NK cells and their targets. This increased adhesion leads to a more efficient killing and enhanced IFN7 secretion. Significance. Since CD72 is expressed on antigen presenting cells (APC) and the CD100-CD72 interaction lead to the shading of CD100, we suggest that NK interacting with APC cells could be the early source of soluble CD100 which is crucial for the formation of antigen specific immune response. CD100-CD72 interaction can be the mechanism by which NK cell communicate with B cells.