Endocannabinoids are endogenous bioactive lipids ubiquitously distributed in several tissues (e.g., brain, adipose tissue, liver, heart and arterial vessels), which play a crucial role in atherosclerosis. Endocannabinoids have been shown to promote cell homeostasis and modulate inflammatory bioactivities mainly via the binding to transmembrane receptors (called cannabinoid type 1 and cannabinoid type 2 receptors, respectively). Although other cannabinoid receptors have been recently identified and shown to play a crucial role in cardiovascular pathophysiology, so far, the pharmacological targeting of both cannabinoid type 1 and cannabinoid type 2 receptors has been described as a promising therapeutic target in atherogenesis and associated inflammatory processes. In particular, endocannabinoids have been shown to modulate the release and activation of matrix degrading enzymes (i.e., matrix metalloproteinases [MMPs]) increasing intraplaque vulnerability. In this article the authors describe the pivotal regulatory activity of the endocannabinoid system on gelatinase (MMP-2 and -9) bioactivity in the arterial wall physiology and pathophysiology.