Pharmacoepidemiology, in the sense of the study of the reciprocal interactions between drugs and populations, was probably conceived far before being named so. However, the modern era started in 1985 with the birth of the International society of pharmacoepidemiology and the development of specific methodological approaches and large databases. This advent of pharmacoepidemiology resulted from a long period where the actual target of medicines, i.e., patients in real-life settings, was not considered, the truth being provided solely by pre-approval or peri-approval clinical trials. The methodological advances made during the last three decades are unprecedented. The challenge is now to avoid focusing excessively on the method to the detriment of pharmacological and public health objectives.