In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines, leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue, two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation and prevents fatty acid accumulation and 'lipotoxicity' in these tissues. On the other hand, under conditions of peripheral leptin resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is also discussed.