Every rodent experiment is based on important parameters concerning the levels of caloric intake and physical activity. In many cases, these decisions are not made consciously, but are based on traditional models. For experimental models directed at the study of caloric intake and activity, the selection of parameters is usually aimed at modeling human conditions, the ultimate goal of which is to gain insight into the pathophysiology of the disease process in man. In each model, it is important to understand the influence of diet, exercise, and genetic background on physiology and the development of disease states. Along the continuum of energy intake from caloric restriction to high-fat feeding, and of energy output from total inactivity to forced exercise, a number of models are used to study different disease states. In this paper, we will evaluate the influence of the quantity and composition of diet and exercise in several animal models, and will discuss how each model can be applied to various human conditions. This review will be limited to traditional models using the rat as the experimental animal, and although it is not an exhaustive list, the models presented are those most commonly represented in the literature. We will also review the mechanisms by which each affects rat physiology, and will compare these to the analogous mechanisms in the modeled human disease state. We hope that the information presented here will help researchers make choices among the available models and will encourage discussion on the interpretation and extrapolation of results obtained from traditional and novel rodent experiments on diet, exercise, and chronic disease.