Abstract: Natural product fragments, biosynthetic intermediates, and chemo-reactive natural products are important resources for drug discovery. The combination of chemical, non-enzymatic or enzymatic coupling reaction between natural product fragments to produce novel skeletons and diverse pseudo-natural products is an effective strategy for the artificial chemical evolution of natural products. These pseudo-natural products may play novel biological functions not possessed by their fragments. The molecular entities generated by the pseudo-natural product-based strategy are similar to small molecule drugs and drug-like molecules, which is in line with Lipinski's rule, and so would be an important supplement for drug discovery. This review summarizes the recent progress in the strategy of pseudo-natural products-driven chemical evolution, focusing on the creation of novel molecules and their novel biological functions.