The endocannabinoid system (ECS) received a lot of attention ever since its discovery. Advancements of the last three decades have shown that there are numerous mechanisms by which the ECS regulates the energy metabolism. These can either be central (regulating appetite and calorie expenditure) or peripheral (adipocyte-specific and other) mechanisms. The current review highlights some of the most important observations leading to the discovery of the ECS first, followed by a part detailing the synthesis and transport of these mediators, the receptor types and second messenger systems involved. The next part is dedicated to the mechanisms by which this system regulates the energy metabolism. Lastly, the drugs that reached the clinical phase and the main targets and strategies for future drug development will be reviewed.