Overexpression of phosphatidylinositol phosphate 5-kinase alpha (PIP5KIalpha), which synthesizes PIP2, suppresses apoptosis, whereas a kinase-deficient mutant does not. Protection by the wild-type PIP5KIalpha isaccompanied by decreases in the generation of activated caspases and of caspase 3-cleaved PARP. Protection is not mediated through PIP3 or Akt activation. An anti-apoptotic role for PIP(2) is substantiated by the finding that PIP5KIalpha is cleaved by caspase 3 during apoptosis, and cleavage inactivates PIP5KIalpha in vitro. Mutation of the P(4) position (D279A) of the PIP5KIalpha caspase 3 cleavage consensus prevents cleavage in vitro, and during apoptosis in vivo. Significantly, the caspase 3-resistant PIP5KIalpha mutant is more effective in suppressing apoptosis than the wild-type kinase. PIP2 is a direct regulator of apical and effector caspases in the death receptor and mitochondrial pathways, and PIP5KIalpha inactivation contributes to the progression of apoptosis.