Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the anti-obesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the ‘Is leptin coming back?’ symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).