Chemoattractants, including chemokines, play a central role in regulation of inflammatory reactions by attracting and activating leukocytes. These molecules have been found to regulate metabolism of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) via phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K). Recent studies of mouse lines that lack PLC-β2, PLC-β3, or PI3Kγ demonstrate that chemoattractants act through PLC-β2 and PLC-β3 to hydrolyze PtdIns(4,5)P₂ and through PI3Kγ to phosphorylate PtdIns(4,5)P₂ in mouse neutrophils. These studies also confirmed the importance and revealed new roles of these signaling pathways in chemoattractant-induced responses.