A substantial body of epidemiologic data has shed light on the potential protective effects of the Mediterranean diet against atherosclerosis in humans. Many believe the reason the Mediterranean diet is atheroprotective is the elevated consumption of olive oil, an oil poor in saturated fatty acids (SFA) and highly enriched in monounsaturated fatty acids (MUFA). Based on human feeding studies, the American Heart Association and the US Food and Drug Administration have advocated for the consumption of MUFA as a more healthy replacement for SFA. However, using experimental animal models in which extent of atherosclerosis can be directly measured following dietary intervention, it has been demonstrated that MUFA-enriched diets are not atheroprotective when compared with SFA-enriched diets. Hence, the current body of experimental evidence refutes the idea that MUFAs per se are atheroprotective; therefore much additional work is needed to determine which aspects of the Mediterranean diet are indeed heart healthy.