Background: Research regarding the health and wellness of medical students has led to ongoing concerns regarding patterns of alcohol and drug use that take place during medical education. Such research, however, is typically limited to single-institution studies or has been conducted over 25 years ago. Objective: The objective of the investigation was to assess the prevalence and consequences of medical student alcohol and drug use and students’ perceptions of their medical school’s substance-use policies. Design: A total of 855 medical students representing 49 medical colleges throughout the United States participated in an online survey between December 2015 and March 2016. Results: Data showed that 91.3% and 26.2% of medical students consumed alcohol and used marijuana respectively in the past year, and 33.8% of medical students consumed five or more drinks in one sitting in the past two weeks. Differences in use emerged regarding demographic characteristics of students. Consequences of alcohol and drug use in this sample of medical students included but were not limited to interpersonal altercations, serious suicidal ideation, cognitive deficits, compromised academic performance, and driving under the influence of substances. Forty percent of medical students reported being unaware of their medical institution’s substance-use policies. Conclusions: Findings suggest that substance use among medical students in the US is ongoing and associated with consequences in various domains. There is a lack of familiarity regarding school substance-use policies. Although there has been some progress in characterizing medical student alcohol use, less is known about the factors surrounding medical students’ use of other substances. Updated, comprehensive studies on the patterns of medical student substance use are needed if we are to make the necessary changes needed to effectively prevent substance-use disorders among medical students and support those who are in need of help.