Abstract: Finding new natural product-based drugs from the resources of traditional Chinese medical herbs can rapidly promote the modernization of traditional Chinese medicine. The bottleneck in the development of natural product based-drugs is their unknown protein targets and unclear mechanisms of action. Recently, a growing number of methods for the target identification of medicinal compounds have emerged, in relation to explicitly reveal their pharmacological mechanisms and toxic side effects. Particularly, mass-based chemoproteomic methods for the target identification, which can be applied with complicated biological models, has the advantages of high reproducibility and high accuracy in indiscriminately determining the protein targets. Since it becomes the most important tool in the discovery of natural product targets, herein we would like to provide a holistic perspective of these chemoproteomic methods, including their principles, pros and cons, the range of application, and representative examples.