The weight loss claims of popular or fad diets are alluring to a public eager to lose weight. The continuously evolving messaging about the optimal way to lose weight results in billions of dollars spent yearly on various diet strategies, many of which are not empirically validated. Health-care professionals historically recommended low-fat (LF) diets to reduce energy intake as a healthy and safe way to lose weight. Over the last decade or so, there has been increased research activity on alternative macronutrient-focused weight loss strategies (i.e., low-carbohydrate [LC] diets, Mediterranean-style diets, etc.). Although energy in, energy out remains the foundation of obesity treatment, the role of macronutrients in weight loss is complex and not fully understood. As such, debate continues regarding the optimal weight loss strategy. This chapter reviews the rationale for macronutrient-based approaches to weight loss and the relative effects of macronutrient and other food characteristics (i.e., glycemic index [GI], energy density) on weight loss among those who suffer from obesity.