The recreational and medicinal desirability of marijuana (Cannabis sativa), fomented by widespread and generationally shifted social acceptance, has created a perfect storm for the medical community. The emergence of this drug highlights the lack of scientific and clinical understanding of its effects, including those that are health adverse as well as medicinal. This review illustrates established findings to guide psychiatric practice (and nonpractice) and outlines open questions to motivate further study. This work provides a general introduction on the properties of marijuana, briefly describes the cannabinoid receptors (cell surface proteins that recognize the plant’s psychoactive constituent, Δ⁹-tetrahydrocannabinol), and delineates the potential utility of agents that activate such receptors. Current theories on the workings of the endogenous neurotransmitter system that is hijacked by Δ⁹-tetrahydrocannabinol are considered. Finally, this review proposes possible ways in which growing knowledge of this system might lead to the discovery of new medicines to treat mental illness.