Metabolic disturbances associated with alterations in lipid metabolism, such as obesity, type 2 diabetes, and syndrome X, are becoming more and more prominent in Western societies. Despite extensive research in such pathologies and their molecular basis, we are still far from completely understanding how these metabolic perturbations are produced and interrelate and, consequently, how to treat them efficiently. The discovery that adipose tissue is, in fact, an endocrine tissue able to secrete active molecules related to lipid homeostasis—the adipokines—has dramatically changed our understanding of the molecular events that take place in such diseases. This knowledge has been further improved by the discovery of peroxisome proliferator-activated receptors and their ligands, at present commonly used for the clinical treatment of lipid disturbances. However, a key point remains to be solved, and that is the role of muscle lipid metabolism, notably because of the main role played by this tissue in the development of such pathologies. In addition, a reciprocal regulation between adipose tissue and skeletal muscle has been proposed. New discoveries on the role of peroxisome proliferator-activated receptor-δ in skeletal muscle functions as well as the secretory capabilities of muscle, now considered as an endocrine tissue, have changed the general point of view on lipid homeostasis, opening new and promising doors for the treatment of lipid disorders.