Although the development of obesity drugs has been plagued by failure, two novel therapies have recently received US Food and Drug Administration approval, the first in 13 years. In their Review, Dietrich and Horvath consider the mechanisms of action of anti-obesity agents, including those currently in use, those withdrawn from the market and new compounds under development. They discuss the role of the hypothalamus in the control of food intake, proposing that agents designed to promote satiety are destined to fail owing to side effects, and suggest how approaches that aim to promote pathways involved in negative energy balance, such as those activated during exercise and calorie restriction, may be more likely to succeed. Leptin, a hormone that is produced by adipose tissue, acts on receptors in the hypothalamus to regulate appetite, body weight and glycaemia. However, although a potentially attractive candidate for the treatment of diabetes and obesity, clinical trials of leptin therapy have been disappointing, largely due to the existence of leptin resistance. Coppari and Bjørbæk review the roles of leptin and our current understanding of the cellular and molecular mechanisms mediating resistance to this hormone. They anticipate that a deeper understanding of this issue will enable the successful development of leptin-based therapeutics. An alternative strategy for treating diabetes and obesity may be the inhibition of autophagy. In fact, dysregulated autophagy has now been implicated in the pathology of a variety of disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. Rubinzstein and colleagues review the mechanisms of autophagy and the role of this pathway in different diseases, as well as strategies for therapeutic modulation.