The ability of Cannabis sativa or its extracts to induce a compelling desire to eat, and to enhance the pleasurable qualities of food, has been well established for centuries. These actions are mediated via central cannabinoid receptors, and reflect a physiological role of the endogenous cannabinoids in the normal control of appetite. In animals, stimulation of CB1 cannabinoid receptors by exogenous agonists (e.g., D9-THC) or by endocannabinoids (anandamide, 2-arachidonoylglycerol and noladin ether) increases the salience of food stimuli, provokes food-seeking behaviour, advances the onset of meal-taking and promotes overconsumption. These actions are obtained at key appetite- and reward-related brain sites, such as the nucleus accumbens shell and hypothalamic nuclei. Changes in nutritional status are also associated with altered endocannabinoid levels in limbic forebrain and hypothalamus. Additionally, endocannabinoid modulation of appetite involves critical interactions with orexigenic neurochemicals such as the opioid peptides, ghrelin and MCH. In line with the behavioural adjustments induced by cannabinoid receptor agonists in animal models, administration of THC in humans accentuates pre-prandial hunger ratings, reduces eating latency, and promotes overconsumption through an increase in the frequency of eating episodes. There is also evidence for critical cannabinoid involvement in the integration of central motivational processes and peripheral mechanisms that regulate fuel storage and energy expenditure. Research into these mechanisms promises to provide important insights into the complex behavioural and physiological processes that govern energy balance, and new treatments for the alleviation of disorders of appetite and body weight, such as cancer cachexia and obesity.