Obesity is a fast growing epidemic that is primarily due to environmental influences. Nutrition and exercise represent modifiable factors with a major impact on energy balance. Despite considerable research, there remains continued debate regarding the energy content and the optimal macronutrient distribution for promoting healthy and effective weight loss. Low-fat diets have been advised for many years to reduce obesity. However, their effectiveness has been recently challenged, partly because the prevalence of obesity continues to rise despite reductions in fat intake. There are also concerns regarding the methodology of clinical trials showing benefits of fat reduction on weight loss. Although often viewed as a fad diet, very low-carbohydrate (ketogenic) diets are very popular and several recent clinical trials indicate they are more effective at promoting short-term weight loss and improving characteristics of the metabolic syndrome than low-fat diets. However, there is a need to obtain long-term safety and efficacy data. Clearly, weight loss can be achieved with a variety of diet interventions but the effects on other health-related aspects also need to be considered and studied in more detail. Exercise can have positive effects on weight loss, weight control and overall general health, although debate exists concerning the most effective mode, duration and intensity of exercise required to achieve these effects. Importantly, any effective weight control treatment must consider a life-long plan or there will likely be weight regain. Perhaps the most challenging, but rewarding, question that faces researchers is how to predict individual responses to diet and exercise interventions.