A Mediterranean diet appears to have health benefits in many domains of human health, mediated perhaps by its anti-inflammatory effects. Metabolism of fatty acids and subsequent eicosanoid production is a key mechanism by which a Mediterranean diet can exert anti-inflammatory effects. Both dietary fatty acids and fatty acid metabolism determine fatty acid availability for cyclooxygenase- and lipoxygenase-dependent production of eicosanoids, namely prostaglandins and leukotrienes. In dietary intervention studies and in observational studies of the Mediterranean diet, blood levels of fatty acids do reflect dietary intakes but are attenuated. Small differences in fatty acid levels, however, appear to be important, especially when exposures occur over long periods of time. This review summarizes how fat intakes from a Greek-style Mediterranean diet can be expected to affect fatty acid metabolizing proteins, with an emphasis on the metabolic pathways that lead to the formation of proinflammatory eicosanoids. The proteins involved in these pathways are ripe for investigation using proteomic approaches and may be targets for colon cancer prevention.