Phospholipase A(2)s (PLA(2)s) are key enzymes that catalyze the hydrolysis of membrane phospholipids to release bioactive lipids that play an important role in normal cellular homeostasis. Under certain circumstances, disrupted production of key lipid mediators may adversely impact physiological processes, leading to pathological conditions such as inflammation and cancer. In particular, cytosolic PLA(2)alpha (cPLA(2)alpha) has a high selectivity for liberating arachidonic acid (AA) that is subsequently metabolized by a panel of downstream enzymes for eicosanoid production. Although concentrations of free AA are maintained at low levels in resting cells, alterations in AA production, often resulting from dysregulation of cPLA(2)alpha activity, are observed in transformed cells. In this review, we summarize recent evidence that cPLA(2)alpha plays a role in the pathogenesis of many human cancers. Much of this evidence has been accumulated from functional studies using cPLA(2)alpha-deficient mice, as well as mechanistic studies in cell culture. We also discuss the potential contribution of cPLA(2)alpha and AA to apoptosis, and the regulatory mechanisms leading to aberrant expression of cPLA(2)alpha.