Two potential approaches for the treatment of obesity are presented, in which modulation of a target increases fatty acid oxidation. These two methods, which are here referred to as 'pull' and 'push' routes, involve creating a demand for fuel by uncoupling oxidation from ATP production ('pulling'), or shuttling fatty acyl CoA into the mitochondria by an afferent mechanism ('pushing'). Proof-of-principle studies in humans are required to assess the use of these approaches in weight loss maintenance.