This article examines the importance of dietary energy density (ED) as a major factor that may influence human appetite and energy intake (EI). The article examines whether the effects of diet composition on appetite and EI can be explained in terms of ED. There is clear evidence that dietary macronutrients exert differential effects on energy intake (EI), both in the laboratory and in real life. Under normal conditions where fat contributes disproportionately to ED, protein, carbohydrate, and fat exert hierarchical effects on satiety in the order protein >carbohydrate > fat. Alcohol appears to stimulate EI. In human appetite studies the main effect of controlling ED is to diminish the impact of differences in the satiating effects of fat and carbohydrate. ED exerts profound effects in constraining EI in short-to-medium term studies. Subjects behave differently in longer term interventions. In short-to-medium term laboratory studies, increases in ED are more effective at increasing EI than at decreasing food intake. In longer term and cross-sectional studies conducted in naturalistic environments, increased ED appears more effective at decreasing food intake and less effective at elevating EI. The available evidence suggests that we should be evolving more complex, multifactor models to account for the observations that both macronutrients and ED affect EI rather than substituting one simplistic model with another.