The Cannabis sativa (marijuana) plant is well known for its mood regulating effects. Since the identification of two cannabinoid (CB) receptors for the plants major active constituent δ9-tetrahydrocannabinol (THC) around 1990, endogenous ligands, the endocannabinoids, have been discovered, leading to the definition of the ‘endocannabinoid-CBreceptor (ECBR) system’. The ligands, including anandamide and 2-arachidonylglycerol, are particularly interesting since they are derivatives of arachidonic acid, while interacting with related lipids such as oleoylethanolamide. During the previous decade, our knowledge and understanding of the ubiquitous presence and functions, as well as dysfunctions of the ECBR system has expanded dramatically. In the current review we will present an updated overview of the physiology, pathology and pharmacology of the ECBR system. Thus we will briefly describe its components (receptors, endocannabinoids, degradative enzymes). Next, we will discuss the involvement of the ECBR system in peripheral organ systems (gastrointestinal, immune, cardiovascular), brain (memory, movement, coordination, reward and addiction) as well as in pain and appetite-related systems. For example, CB1 and CB2 receptors mediate relaxation of the intestinal system and exert anti-inflammatory effects, while activating CB1 receptors enhances appetite and food intake and is critical for suckling in newborn mice. The third section will be devoted to the ECBR role in reproduction and perinatal development. Finally, pathophysiological issues and therapeutic potential will be discussed, based on the physiological functions ascribed to the ECBR system, such as cannabinoid-based therapies for irritable bowel disease, food-disorders and neuropsychiatric disturbances. Hopefully the next decade will witness its medicinal application of the ECBR system for the benefit of patients suffering from a variety of conditions.