Cellular levels of free arachidonic acid (AA) are tightly controlled through enzymatic release of the fatty acid and subsequent utilization by downstream enzymes including the cyclooxygenases (COXs). Disruption of AA balance has been shown to impact several biological processes, including cancer. Here we demonstrate that limiting the release of arachidonic acid, through genetic deletion of cytoplasmic phospholipase A2 (cPLA2), in fact compromises an important tumor surveillance mechanism (i.e. apoptosis), which otherwise affords partial protection to the colonic epithelium against tumor development. In our study, we observed a pattern of remarkably enhanced colon tumorigenesis in mice with cPLA2 deletions, a phenomenon that occurred despite lower PGE2 levels. This data suggests that the pro-apoptotic role of cPLA2 in the colon predominates over its contribution to eicosanoid biosynthesis. We further showed that limiting AA utilization with the COX-2 inhibitor, rofecoxib (Vioxx®), effectively suppressed colon tumorigenesis in both cPLA2 wild-type and heterozygous mice. In this model, rofecoxib reduced PGE2 levels in the colon to a comparable extent regardless of cPLA2 status, although apoptosis remained unaffected by rofecoxib treatment. Interestingly, we found exposure to rofecoxib to be acutely lethal in the cPLA2 null mice. Toxicity extended to other non-aspirin NSAIDs, including celecoxib (Celebrex®) and sulindac (Clinoril®), yet was partially overcome by co-administration of clopidogrel (Plavix ®). The lethality response to these NSAIDs was associated with cardiac fibrosis, degeneration and necrosis as well as early signs of renal failure. Collectively, these studies illustrate downstream effects of disrupting AA homeostasis with regard to tumor development and treatment.