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Clostridium spp. are important microorganisms that can degrade complex biomasses such as lignocellulose, which is a widespread and renewable natural resource. Co-culturing Clostridium spp. and other microorganisms is considered to be a promising strategy for utilizing renewable feed stocks and has been widely used in biotechnology to produce bio-fuels and bio-solvents. In this review, we summarize recent progress on the Clostridium co-culture system, including system unique advantages, composition, products, and interaction mechanisms. In addition, biochemical regulation and genetic modifications used to improve the Clostridium co-culture system are also summarized. Finally, future prospects for Clostridium co-culture systems are discussed in light of recent progress, challenges, and trends.