Professional cycling is globally recognized for its impressive physical performances. However, cycling also has the reputation of having one of the worst problems of illicit performance enhancement among its athletes. Performance enhancement, in the context of sports, is the use of external means to enhance an individual’s physical abilities to perform. Methods of enhancement range from skillful training, technological assistance, genetic enhancement, dietary modification, and pharmaceutical assistance. Although there are a number of sports commonly associated with performance enhancement methods (PEMs), a historical examination of professional cycling, and in particular, the Tour de France, illuminates several key trends that have made it particularly susceptible to these questionable behaviors, including increased competition, commercialization, and integration of medical knowledge and expertise.