The therapeutic properties of cannabis have been recognized for thousands of years. The main active compounds in cannabis that have been scientifically proven to possess pharmacological properties are tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD). Cannabinoids have been found to serve diverse functions in physiological processes and are recognized for their properties including but not limited to, appetite stimulation, pain relief, anticonvulsant effects, bronchodilation, sedation, hypnotic effects, and muscle relaxation. In general, cannabinoids exhibit a favorable safety profile as pharmaceutical agents. However, interaction with drug-metabolizing enzymes, including the cytochrome P450 (CYP) family and P-glycoprotein (P-gp), alters the metabolism of co-administered drugs that are also metabolized by these enzymes. This article focuses on the challenges and recent progress in understanding the interactions between cannabis and other drugs, which can be influenced by membrane efflux transporters, CYP, and other drug metabolism enzymes. Given the increasing prevalence of cannabis use and the limited knowledge regarding cannabinoid-drug interactions, further research is necessary to explore the effects of cannabinoids on concurrent drug use.