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Cannabinoid receptors in hominids co\u2010evolved with diet, and the ECS constitutes a feedback loop for food selection and energy metabolism. Here, it is postulated that the mismatch of ancient lipid genes of hunter\u2010gatherers and pastoralists with the high\u2010carbohydrate diet introduced by agriculture could be compensated for via dietary modulation of the ECS. In addition to the fatty acid precursors of endocannabinoids, the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed. Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid\u2010type 2 (CB<jats:sub>2<\/jats:sub>) receptors may provide adaptive metabolic advantages and counteract inflammation. In contrast, chronic CB<jats:sub>1<\/jats:sub>receptor activation in hedonic obese individuals may enhance pathophysiological processes related to hyperlipidaemia, diabetes, hepatorenal inflammation and cardiometabolic risk. Food able to modulate the CB<jats:sub>1<\/jats:sub>\/CB<jats:sub>2<\/jats:sub>receptor activation ratio may thus play a role in the nutrition transition of Western high\u2010calorie diets. In this review, the interplay between diet and the ECS is highlighted from an evolutionary perspective. The emerging potential of cannabimimetic food as a nutraceutical strategy is critically discussed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. 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