The endocannabinoid system regulates the energy balance in the brain, as well as in the periphery. The endocannabinoid system also controls several physiological conditions. It is composed of anandamide and 2-arachidonoylglycerol, which are the endogenic ligands for cannabinoid receptor type 1 and cannabinoid receptor type 2, respectively, and enzymes such as N-acyl phosphatidyl ethanolamine phospholipase D, mono- and diacyl glycerol lipase, and amide hydrolase. The endocannabinoid system participates in the production, degradation, and uptake of endocannabinoids. The endocannabinoid system is an endogenous neuroprotective system that controls emotion and cognition either through receptor-mediated or non-receptor-mediated mechanisms. Cannabinoid receptors type 1 or 2 are selectively targeted in the treatment of disorders related to Alzheimer’s disease, Parkinson’s disease, cognition, Huntington’s disease, psychosis, anxiety, depression, and aging. The present chapter attempts to give evidence for the contribution of the endocannabinoid signaling system in neurocognitive dysfunctions, treatment strategies, and preclinical and clinical representations. © 2023 Taylor & Francis Group, LLC.