A major remark made by observers relates to the focus of the pharmaceutical industry on ‘me-too’ drugs rather than ‘first-in-class’ drugs, the latter are considered to be ‘truly’ innovative medicines. Although the subject is heavily debated, chemists in project teams around the globe are routinely following up compounds from competitors. An important strategic consideration is the degree of chemical modification of the original structure required for success.Here,we present an analysis of the DiMasi and Faden set of first-in-class and follow-on drug pairs (n = 74); showing that 70%of them are structurally very similar, meaning that they are characterized by minimal structural variations. This highlights the fact that even simple atomic variations can cause drastic changes in molecular properties responsible for therapeutic advantages.