The progression of acute-on-chronic liver failure (ACLF) is associated with various factors, including inflammatory cells, cytokines, inflammatory mediators, and the gut microbiome. Acute insult activates immune cells which provokes cytokine and chemokine cascades and subsequently initiates hepatic damage, aggressive systemic inflammatory response syndrome (SIRS), and high mortality in patients with ACLF. Immune soluble components not only play a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh score, the model for end-stage liver disease (MELD) score, and sequential organ failure (SOF) score. Several immune soluble components lead to a better understanding of the pathophysiological basis of ACLF, and precise immune mechanisms offer therapeutic targets for ACLF. However, there are a number of specific issues that were not addressed unambiguously, such as whether dysfunctional immune soluble components are the cause or outcome of ACLF. Further evaluation and validation of emerging and relevant biomarkers will facilitate the formulation of a potential score which, either alone or in combination with existing scoring systems, will improve the clinical outcome prognostication and therapeutic efficacy of patients with ACLF. Extensive research is required to find out the mechanisms responsible for disease severity and high mortality in patients with ACLF.