Maintenance of body temperature is achieved partly by modulating lipolysis by a network of complex regulatory mechanisms. Lipolysis is an integral part of the glycerolipid/free fatty acid (GL/FFA) cycle, which is the focus of this review, and we discuss the significance of this pathway in the regulation of many physiological processes besides thermogenesis. GL/FFA cycle is referred to as a "futile" cycle because it involves continuous formation and hydrolysis of GL with the release of heat, at the expense of ATP. However, we present evidence underscoring the "vital" cellular signaling roles of the GL/FFA cycle for many biological processes. Probably because of its importance in many cellular functions, GL/FFA cycling is under stringent control and is organized as several composite short substrate/product cycles where forward and backward reactions are catalyzed by separate enzymes. We believe that the renaissance of the GL/FFA cycle is timely, considering the emerging view that many of the neutral lipids are in fact key signaling molecules whose production is closely linked to GL/FFA cycling processes. The evidence supporting the view that alterations in GL/FFA cycling are involved in the pathogenesis of "fatal" conditions such as obesity, type 2 diabetes, and cancer is discussed. We also review the different enzymatic and transport steps that encompass the GL/FFA cycle leading to the generation of several metabolic signals possibly implicated in the regulation of biological processes ranging from energy homeostasis, insulin secretion and appetite control to aging and longevity. Finally, we present a perspective of the possible therapeutic implications of targeting this cycling.