Discovery of new natural products, especially those with high biological activities and application values, is of great research significance. However, conventional methods based on the cultivation of microbial mono-cultures can hardly satisfy the increasing need of novel natural product generation. Recently, the development of co-cultures composed of different species has emerged as an effective approach for mining novel natural products. Inspired by microbial communities in nature, these co-culture systems create favorable environmental conditions to promote interactions between co-culture members for activating the natural product biosynthesis that is hard to induce otherwise. A large variety of novel natural products have been identified using this robust approach. This review summarizes the recent achievements of using cross-species co-cultures for natural products discovery and discusses the existing challenges and future directions.