Abstract: Follow-on drug approach is to follow-up and make-up of the innovation of pioneering drugs. Since the millennium new molecular entities (NME) have experienced ample optimization, and the patents have claimed in wide ranges, as well as the drug administration requires NME being superior or non-inferior to the existing drugs of the same class. These situations have made the space of follow-on drug innovation narrow and smaller than before. The follow-on drug approach can be concisely differentiated into two aspects:one is to start from the chemistry of small molecules, which are performed with a niche-targeting manipulation to optimize the safety, efficacy and (or) convenience for dose superior to the existing drugs; another proceeds with the macromolecule targets. Based on the knowledge of the mechanism of action or of target mutation, active compounds are constructed through complementary binding or by the reaction mechanism. In this article successful examples are briefly described to illustrate the features of follow-on drug approach.