The Zone Diet was developed on the concept that the hormonal responses of macronutrients could be orchestrated to maintain key hormones within therapeutic zones to control inflammatory responses. In particular, the two hormonal systems that are directly affected by dietary macronutrients are (1) the insulin/glucagon axis and (2) eicosanoids. Each of these hormonal systems can have a significant impact on the inflammatory process. This hormonal approach to optimizing an anti-inflammatory diet has significant ramifications in treatment of those chronic diseases (obesity, type 2 diabetes, and cardiovascular disease) that are known to produce inflammatory responses. On the other hand, an inappropriate balance of macronutrients (especially high glycemic- load carbohydrates) can lead to increased inflammation. A primary example of this is the promotion of the United States Department of Agriculture's Food Guide Pyramid. Since its adoption, the prevalence of obesity and type 2 diabetes has risen substantially. Both conditions also demonstrate a significant increase in inflammatory markers. The purpose of this article is to review the historical factors that led to the development of the Zone Diet, to understand how the Zone Diet can alter inflammatory responses, and to review the published literature on its ability to affect hormonal and metabolic responses.