This chapter provides an overview of developments in understanding of the impact of cannabis on the human brain. The rich historical experience of the medicinal and psychoactive properties of cannabis underpins current investigations into the potential of modulating the endocannabinoid system for therapeutic purposes. Clinical and epidemiological data link cannabis use both beneficially and detrimentally to a variety of neuropsychiatric disorders including schizophrenia and psychosis, mood, anxiety, substance use, movement, pain, eating, and cognitive disorders. The elucidation of the Cannabinoid receptor 1 (CB1R) as the primary nervous system cannabinoid receptor, its endogenous ligands and their synthetic and degradative machinery has permitted investigation of the endocannabinoid system, and the modulation of this system for therapeutic gains. In neurons it appears to underpin an activity-dependent retrograde signaling system that dampens synaptic transmission. The therapeutic use of cannabinoids including cannabis and dronabinol is widespread for disorders such as cancer and chronic pain, appetite stimulation in cachexia and muscle spasticity. It is found that agents that amplify the endogenous cannabinoid signal by decreasing hydrolysis of AA show promising effects in a range of disorders albeit at an animal model stage.