Marijuana is the most commonly used, cultivated, and trafficked illicit drug worldwide. In the United States, the use and acceptance of marijuana is evolving rapidly as indicated by the volume of new state cannabis legislation. However, marijuana is still a Schedule I drug under the federal Controlled Substances Act (CSA). Further complicating the matter, the 2018 Farm Bill removed hemp from the list of controlled substances under the CSA, resulting in a market flooded with cannabidiol (CBD) products that have not been approved by the Food and Drug Administration (FDA). Many of the changes in state laws have occurred without significant input from medical or scientific communities. The status of marijuana and, until recently, hemp as Schedule I drugs under the CSA creates numerous restrictions which ultimately impact the industry as a whole. The central issues facing marijuana legality in the U.S. are: convoluted state and federal law, adverse health effects of cannabis use, research restrictions that produce knowledge gaps, and inconsistency between the U.S. Food and Drug Administration (FDA) and the U.S. Environmental Protection Agency (EPA) regulations. Marijuana policy must evolve to protect and inform both the general public and individuals involved in the cannabis industry. Potential reform options include: federal exemptions following state compliance, rescheduling marijuana, or complete removal from the CSA. The most vital step in the federal legalization process needs to be less restrictive research opportunities for marijuana.