With the rising prevalence of both obesity and diabetes, the contributing role of diet to the prevention and treatment of these conditions has become a major focus of research, clinical practice, and public policy. There has been intense debate over which dietary regimens might be most effective for weight loss, with interest centered on the potential for specific dietary macronutrients to affect body composition, metabolism, and overall health. This Review addresses two regimens with distinct macronutrient prescriptions that have been widely touted as being beneficial for weight loss and/or metabolic profile: diets low in carbohydrate and diets high in monounsaturated fat. Although data from recent randomized, controlled trials suggest these popular diets may be useful for weight control, cardiovascular health, and glycemic control, longer studies of the efficacy and safety of varying macronutrient content are needed to strengthen the evidence base for nutritional recommendations. Until more support for specific macronutrient combinations is available, practitioners can recommend an array of diets with moderate amounts of macronutrients, tailored to individual needs and preferences.