Rho GTPases including Rho, Rac, and Cdc42 act as intracellular molecular switches to control cellular responses such as actin cytoskeleton rearrangement, gene transcription, cell growth, and possibly transformation. Their roles have been increasingly implicated in activation of signaling processes in leukocytes including integrin-mediated signal transduction and growth factor-induced cell survival and proliferation pathways. In particular, functional disruption of Rac2, a hematopoietic-specific Rho GTPase, causes severe myeloid cell dysfunction in both mouse and man. Rac2-deficient mice and a human patient with a D57N Rac2 mutant share a phenotype of leukocytosis with defective neutrophil chemotaxis and superoxide production in response to some, but not all, agonists. Our studies also suggested that the phenotypic abnormalities associated with D57N may involve not only neutrophil cellular functions, but also abnormal cell survival in other hematopoietic cells. Together, these data demonstrate a critical and unique role for Rac2 in normal neutrophil function and define a new genetic immunodeficiency syndrome in humans.