Obesity is a complex multifactorial disease involving energy balance and metabolism, both in its pathogenesis and in its complications. Endocrine function plays a key role in this context, and research has, in fact, provided increasing evidence of alterations of hormonal factors in obesity, as well as of their clinical relevance also as therapeutic targets. Obesity may be associated with alterations in all major networks involved in nutritional and metabolic control, including gastrointestinal sensing by gut hormones, endocrine factors release from related organs such as pancreas and liver, as well as factors released from the adipose organ. The central nervous system (CNS) is also a key player, being involved in integrating afferent signaling with hedonistic and voluntary pathways, finally modulating orexigenic and anorexigenic circuits. CNS control of obesity-related mechanisms is then translated into peripheral metabolic control, again through efferent endocrine signaling axes as well as by sympathetic nervous system modulation. Importantly, evidence shows that afferent and efferent signaling are strictly interlinked, with several homeostatic feedback loops which, while providing efficient energy homeostatic control in physiologic conditions, may pose further challenges in obesity management. This chapter aims at presenting updated knowledge on the main endocrine factors involved in obesity physiopathology as well as their role in therapeutic strategies for this chronic disease.