Abstract: In nature, microorganisms do not exist solely but in communities. They constantly shape ecological niches to achieve coevolution via interaction with each other and with surrounding organisms. Secondary metabolites are synthesized as communication languages or chemical weapons to adapt themselves to variable environments driven by microbial interactions and become an important source of drug discovery. Microbial cocultivation simulates natural ecological relationships, triggering silent biosynthesis gene clusters and promoting the discovery of novel natural products. Here, this review introduces the recent advances in the discovery of bioactive natural products via different cocultivation systems, especially the mechanisms for microbial interaction and silent gene cluster activation, aiming to provide some reference for mining the chemical diversity of natural microbial products.