The signaling pathways that regulate B and T lymphocytes are remarkably conserved between humans and mice. However, recent evidence suggests that the pathways regulating natural killer (NK) cell activation may actually differ between these two species. We discuss the controversies in the field and propose that this divergence could be deceptive: despite some clear differences between human and mouse NK cell receptors, the many ways of activating NK cells and their functions may well be conserved.