The innovation of Chinese materia medica (CMM) is the soul of traditional Chinese medicine (TCM) modernization and internationalization. The application of modern theories and techniques in life sciences and medicine to innovative CMM research remains to be an urgent issue to be solved in TCM research area. This paper summarizes and generalizes six main R&D models for CMM innovation according to the nearly one century of history and experiences accumulated in TCM research in China and referencing to the idea and philosophy of natural product study in Western countries as well. The nomenclature of these models is based on several successful drug discovery examples in TCM, such as the artemisinin model, the culture medium model, the GBE761-Veregen model, the PHY906 model, the Compound Danshen Dripping Pills model, and the PC-SPES model. The application, characteristics, advantages, disadvantages, and the development prospect of each model in TCM R&D have been Reviewed.