Multiple homeostatic and hedonic control centers of food intake express δ-, κ-, and/or μ-opioid receptors as well as cannabinoid receptor type 1. Endogenous opioids such as enkephalins, endorphins, or dynorphins are important in our response to and moderation of pain and pleasure, and influence both homeostatic and hedonic aspects of eating behavior. Similar actions on food intake are reported for endocannabinoids such as anandamide or 2-arachidonoylglcerol. Accordingly, both systems have been at the focus of the development of antiobesity drugs based on receptor antagonists. To date, only the μ/κ-opioid receptor antagonist naltrexone and the type 1 cannabinoid receptor (CB₁R) antagonist rimonabant have gained market access as weight loss drugs, but psychiatric liabilities led to withdrawal of rimonabant. On presynaptic neurons, both drugs act via inhibition of presynaptic intracellular calcium influx and/or potassium efflux, which ultimately blocks calcium-dependent neurotransmitter vesicle release. Postsynaptically, the antagonist naltrexone inhibits μ- and to a lesser extent κ-opioid signaling to decrease neuronal activity. Rimonabant and naltrexone may further activate astrocyte cannabinoid and opioid signaling to modulate both presynaptic and postsynaptic neuronal processes.