Secretory phospholipase A2 (sPLA2) behaves differently toward the membranes of healthy cells compared to those of damaged or dying cells. The enzyme catalyzes rapid and sustained hydrolysis of compromised cells consistent with a simple catalytic mechanism. In contrast, when healthy cells are incubated with sPLA2, they become resistant to hydrolytic attack as manifest by three unusual observations: First, hydrolysis is transient and represents only a small fraction of the total membrane phospholipid content. Second, subsequent addition of sPLA2 fails to generate additional product. Third, the apparent potency of the enzyme to cause the membrane to be refractory is much greater than the potency for catalyzing hydrolysis. The mechanism responsible for this resistance has not yet been identified. Using Monte Carlo and direct analytical methods, we have developed a model capable of explaining all three of these observations. The model requires two salient elements: only a small pool of phospholipids in the healthy cell membrane is available for catalysis by sPLA2, and hydrolyzed phospholipids are re-acylated and restored very slowly to the accessible pool. The requirement for initial hydrolysis (as opposed to the simple physical presence of the enzyme as previously thought) was confirmed experimentally. Additional evidence has shown that the membrane does not remain permanently in its resistant state. Over time, the membrane resets to its original state. The model also predicts that total substrate, reacylation rate, and the return rate of phospholipids to the membrane should all be constant as enzyme concentration is varied. This prediction was tested by quantitative analysis of hydrolysis time courses at varied enzyme concentrations. Experiments with fluorescent probes, merocyanine 540 and laurdan suggest, that resistance may also involve physical changes to the membrane beyond the kinetic mechanisms hypothesized in the model.