The pharmacological treatment options for obesity are currently very limited but the prevalence of the disease is increasing rapidly. Obesity has many serious sequelae, the most common of which is type-2-diabetes. The benefits of weight loss on health are established but the major impediment to weight loss treatments is maintenance of weight lost over the long term. The reduced- or post-obese individual undergoes physiological changes that are geared towards energy storage and weight regain. One of the physiological changes is a reduced capacity to oxidise fatty acids pushing them through pathways of triacylglycerol synthesis. In this review, some of the past drug treatments aimed at increasing energy expenditure, such as dinitrophenol and ephedrine, are discussed. Current, or nearly current therapies such as sibutramine and rimonabant are also discussed in the context of increased energy expenditure. The main part of the review focuses on future prospects with discussion around a selection of targets with potential in energy expenditure that lie in pathways with AMP-kinase at their centre and ending at the mitochondrion.