Chronic liver disease, depicted by gradual destruction and fibrosis of the liver, is a condition with high and probably increasing prevalence worldwide. Its deterioration, acute-on-chronic liver failure (ACLF), is characterized by an in-hospital mortality of up to 65%. Infectious complications are the main precipitants eliciting ACLF and concurrently the main cause of death from ACLF. Patients have a marked susceptibility to bacterial infections, which is thought to arise a consequence of an inadequate immune response to microbial challenge, termed immuneparesis. The pathophysiologic mechanisms remain poorly understood. Treatments aimed at restoring the patients’ immune function may prevent onset of ACLF and death from secondary infections. A number of drugs approved for patients with liver disease bear immunomodulatory potential such as albumin, glucocorticoids, N-acetylcysteine. Specific targets have been defined that may lead to development of new immunotherapeutic agents. Here, we summarize the pathophysiology of immuneparesis in ACLF and drug candidates to restore immune function and improve survival in the future.