The use of legal and illegal substances by medical students is a phenomenon that is only partially known. The aim of this paper was to review the literature published internationally in the last 25 years about the use of legal and illegal substances by medical students. A systematic search was made of MEDLINE and LILACS. One hundred and six manuscripts were evaluated, which included a population of 88,413 medical students. We validated 74,001 questionnaires, which represented 83.7% of responses. The methodology and the rigor of its application are not the same in all the publications. There are many regional variations, most studies being made in America and Europe. With the exception of alcohol in some areas of the Western world, medical students use substances less than university students in general and the general population. The substances used are mainly alcohol (24%), tobacco (17.2%), and cannabis (11.8%). The use of hypnotic and sedative drugs also is common (9.9%). The rate of use of stimulants is 7.7% and of cocaine, 2.1%; opiate use being very low (0.4%). In some parts of Latin America, up to 14.1% use inhalants. Students in the last years of school have a higher rate of substance use. The use of substances, except for hypnotics and sedatives, is more common among men than women. The use of substances by medical students is a phenomenon that should be evaluated systematically due to its prevalence and potential impact.