The rising tide of obesity is one of the most pressing health issues of our time, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Fortunately, a recent burgeoning of mechanistic insights into the neuroendocrine regulation of body weight provides an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceuticals. In this review, we articulate a set of conceptual principles that we feel could help prioritize among these molecules in the development of obesity therapeutics, based on an understanding of energy homeostasis. We focus primarily on central targets, highlighting selected strategies to stimulate endogenous catabolic signals or inhibit anabolic signals. Examples of the former approach include methods to enhance central leptin signaling through intranasal leptin delivery, use of superpotent leptin-receptor agonists, and mechanisms to increase leptin sensitivity by manipulating SOCS-3, PTP-1B, ciliary neurotrophic factor, or simply by first losing weight with traditional interventions. Techniques to augment signaling by neurochemical mediators of leptin action that lie downstream of at least some levels of obesity-associated leptin resistance include activation of melanocortin receptors or 5-HT2C and 5-HT1B receptors. We also describe strategies to inhibit anabolic molecules, such as neuropeptide Y, melanin-concentrating hormone, ghrelin, and endocannabinoids. Modulation of gastrointestinal satiation and hunger signals is discussed as well. As scientists continue to provide fundamental insights into the mechanisms governing body weight, the future looks bright for development of new and better antiobesity medications to be used with diet and exercise to facilitate substantial weight loss.