Class substitution is the substitution of a drug by another cheaper drug from the same pharmacological drug class to save costs. This principle is applied in drug formularies and reference-based drug-pricing systems. Class substitution should not only consider similarities in pharmacological mechanisms of action but should also assess whether the different drugs within the class are equivalent at a population level with respect to efficacy, effectiveness, applicability, and safety. The implementation of class substitution requires protocols as well as a monitoring system to evaluate compliance with the protocols and their effects on drug costs. In addition, specific studies are needed to establish whether undesirable effects occur at the patient level.