The scientific knowledge regarding the modulation of the endogenous cannabinoid system and its effect on disease pathophysiology has been significantly improved in the last 20 years. Alterations in the expression of cannabinoid receptors, their main endogenous ligands (arachidonoylethanolamide and 2‐arachidonoylglycerol), and related enzyme levels have been reported in different disease states, suggesting their important regulatory role. The pharmacological effects of synthetic compounds that selectively target the endocannabinoid system, established cause‐effect relationships between endocannabinoids and the progress of several disorders. In this review, the importance of endocannabinoid system modulation and also the aspects of the underlying pathways leading to disease or target organ toxicity are reported.