The endocannabinoid system (ECS) consists of two receptors (CB1 and CB2), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS has deep phylogenetic roots and regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways (e.g., ghrelin, leptin, orexin, adiponectin, endogenous opioids, and corticotropin-releasing hormone). Obesity leads to excessive endocannabinoid production by adipocytes, which drives CB1 in a feed-forward dysfunction. Phylogenetic research suggests the genes for endocannabinoid enzymes, especially DAGLα and NAPE-PLD, may harbor mildly deleterious alleles that express disease-related phenotypes. Several CB1 inverse agonists have been developed for the treatment of obesity, including rimonabant, taranabant, and surinabant. These drugs are efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors. However, given the myriad beneficial roles of the ECS, it should be no surprise that systemic CB1 blockade induces various adverse effects. Alternatives to systemic blockade include CB1 partial agonists, pleiotropic drugs, peripherally restricted antagonists, allosteric antagonists, and endocannabinoid ligand modulation. The ECS offers several discrete targets for the management of obesity and its associated cardiometabolic sequelae.