The hormones insulin and leptin have been demonstrated to act in the central nervous system (CNS) as regulators of energy homeostasis, acting at medial hypothalamic sites. In a previous review (2003) we described new research demonstrating that in addition to these direct homeostatic actions at the hypothalamus, CNS circuitry that subserves reward and motivation is also a direct and indirect target for insulin and leptin action. Specifically, insulin and leptin can decrease food reward behaviors and modulate the function of neurotransmitter systems and neural circuitry that mediate food reward, i.e., midbrain dopamine (DA) and opioidergic pathways. Here we provide an update, summarizing new behavioral, systems, and cellular evidence in support of this hypothesis, and in the context of research into the homeostatic roles of both hormones in the CNS. We discuss some current issues in the field, which should provide additional insight into this hypothetical model. The understanding of neuroendocrine modulation of food reward, as well as food reward modulation by diet and obesity, may point to new directions for therapeutic approaches to overeating or eating disorders.