Because leptin reduces food intake and body weight, the coexistence of elevated leptin levels with obesity is widely interpreted as evidence of ‘leptin resistance.' Indeed, obesity promotes a number of cellular processes that attenuate leptin signaling (referred to here as ‘cellular leptin resistance') and amplify the extent of weight gain induced by genetic and environmental factors. As commonly used, however, the term ‘leptin resistance' embraces a range of phenomena that are distinct in underlying mechanisms and pathophysiological implications. Moreover, the induction of cellular leptin resistance by obesity complicates efforts to distinguish the mechanisms that predispose to weight gain from those that result from it. We suggest a framework for approaching these issues and important avenues for future investigation.