Obesity is a complex disease that is regulated by both central and peripheral mechanisms. New medicines for the treatment and prevention of obesity will need to overcome the powerful compensatory responses of the overlapping, and often redundant, networks that have evolved to safeguard efficient energy use. Despite great progress in the identification of central signals that regulate satiety, and considerable investment in the development of appetite-controlling medications, success has been modest so far. Here we review the main enzymes that are involved in different stages of lipid metabolism -- from digestion and absorption through synthesis and storage to mobilization and oxidation -- which might be successfully targeted by new pharmacotherapies.