Exercise is a valuable tool in the prevention and treatment of cardiometabolic diseases like obesity and type 2 diabetes. Interestingly, endocannabinoids (eCBs), involved in a large range of physiological processes, are elevated with both obesity and acute exercise. In this review we outline this paradox overlap in the context of metabolic health and delineate the transcriptomic response of skeletal muscle to acute and chronic aerobic and resistance exercise in relation to the endocannabinoid system by utilizing a meta-analyses tool. We show that exercise modulates the expression of receptors and enzymes involved in the synthesis and breakdown of eCBs and discuss that eCBs possibly interfere with the anti-inflammatory effect of exercise. The endocannabinoid system (ECS), consisting of certain endogenous lipids (i.e. endocannabinoids), their receptors and associated metabolic enzymes, is involved in the modulation of a plethora of cognitive and physiological processes. Besides its role in the control of, for example, mood formation and immune responses, the ECS takes part in the regulation of appetite and energy metabolism [1,2]. In this current opinion review we will focus on the increased activity of the ECS that is associated with cardiometabolic diseases like obesity and type 2 diabetes (T2D), which paradoxically overlaps with the acute physiological response to exercise. After 1) outlining the role of the ECS in metabolic health, we will 2) discuss the link between endocannabinoid (eCB) action in skeletal muscle and cardiometabolic disease, 3) investigate how exercise modulates the gene expression of ECS components in skeletal muscle and 4) delineate the impact of the ECS on the immune response by skeletal muscle.Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.