The gut dysbiosis is closely associated with the development and progression of many diseases. Therefore, targeting gut microbiome has become an important strategy for disease prevention and treatment. Meanwhile, gut microbiome is probably an important way to understand the modern scientific connotation of traditional Chinese medicine. TCM formulae are usually taken orally, in which the chemical components within in TCM formulae will inevitably interact with gut microbiome producing functional metabolites or being metabolized by gut microbiota, which is often the key to their efficacy. Traditional Chinese medicine can restore the gut microbiome under the diseased condition and play a role in the treatment by promoting the proliferation of beneficial bacteria or inhibiting pathogenic bacteria, and increasing the production of metabolites such as SCFA; Besides, the metabolic transformation of gut microbiota can affect the efficacy of TCM and result in toxicity. Therefore, in this paper, we proposed the “Three Models” hypothesis for understanding the interaction among TCM formulae, gut microbiome and host, i.e., the responsive model of microbiome, the microbiome-dependent model and the microbiome metabolism model, and also discussed the opportunity and challenge of current research on gut microbiome.