The modernization and globalization of traditional Chinese medicines (TCMs) require the implementation of a robust quality control system, and the application of modern theories and technologies in analytical chemistry can greatly facilitate the establishment of such a system. However, inherent “uncertainties” are often present in the chemical measurement data obtained from TCMs using modern analytical instruments. To address this issue, the utilization and further develop-ment of Chemometrics are urgently needed. It plays a crucial role in reducing or eliminating the “uncertainties” associated with the chemical composition, struc-ture, and other relevant information of the TCMs, primarily focusing on qualita-tive identification and quantitative determination. Given that TCMs are complex multi-component systems, future quality evaluation may encompass in silico prediction of physical/chemical properties and activities. Furthermore, it is essential to establish a link between the measured data and biological activity. Achieving these objectives necessitates continuous advancements in Chemometrics and close collab-oration with artificial intelligence. In essence, the quality control of TCMs requires extensive knowledge of Chemometrics, both existing and yet to be explored. This chapter provides a comprehensive discussion on various topics, including “sampling for analytical purposes,” “experimental design and optimization,” “evaluation of experimental measurements,” “fingerprint pre-processing,” “multivariate calibration and multivariate resolution,” “pattern recognition of fingerprint data,” “fingerprint-efficacy modeling,” “structure–property/activity relationship,” and “expert system of TCMs fingerprint.”