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Δ-tetrahydrocannabinol (THC) and its sibling, cannabidiol (CBD), are produced by the same Cannabis plant and have similar chemical structures but differ dramatically in their mechanisms of action and effects on brain functions. Both THC and CBD exhibit promising therapeutic properties; however, impairments and increased incidence of mental health diseases are associated with acute and chronic THC use, respectively, and significant side effects are associated with chronic use of high-dose CBD. This review covers recent molecular and preclinical discoveries concerning the distinct mechanisms of action and bioactivities of THC and CBD and their impact on human behavior and diseases. These discoveries provide a foundation for the development of cannabinoid-based therapeutics for multiple devastating diseases and to assure their safe use in the growing legal market of Cannabis-based products.