Microbial secondary metabolites have been an important source of drugs and their leading compounds because of their novel chemical structures and various biological activities. However, in recent years, there is a high frequency of re-discovery and a low frequency of new discovery of active compounds from microbial pure culture. As microbial co-culture is closer to the natural environment of microbial growth, it plays an important role in new compound mining. Here, we review the progress of new compound mining through co-culture from fungi vs fungi and fungi vs bacteria, and the current problems of this field for future research is also mentioned.