Background: This is the first ever decade which has witnessed the emergence of a highly lethal condition termed acute-on-chronic liver failure (ACLF), which today is the leading cause of death compared to acute and chronic liver failure. However, the complex pathophysiology of ACLF remains poorly understood. This article will attempt to summarize recent progress in the understanding of the mechanisms of cytokines in ACLF. Methods: The search terms used on PubMed were cytokines, liver injury, complications of liver disease, and hepatic progenitor cell. Results: Cytokines play a significant role in the pathophysiology of ACLF including hepatocellular death, extrahepatic complications and hepatocyte regeneration. The tissue-damaging mechanisms of cytokines are closely related to their hepatocyte proliferation and regeneration function. Conclusions: It remains a challenge to selectively prevent the detrimental effects of cytokines. To design interventions which selectively target the detrimental effects of cytokines, a detailed understanding of cytokines in the pathophysiology ACLF is critical.