Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality in patients with chronic liver disease. The definition of ACLF has been addressed recently in many publications, and despite regional differences the number and severity of organ failures are decisive for the presence and severity of ACLF. However, the predisposition of patients to develop ACLF has not been addressed in prospective studies. Several predisposing factors for ACLF have been mentioned, but still clear-cut analysis and the sequential processes have not been explored. One reason is that different factors might predispose in one setting and might be the precipitating event in another, thus rendering the generalization of predisposing factors difficult. However, genetic factors, lifestyle, past medical history, aging, latent chronic infections, and the severity of the liver disease and portal hypertension might predispose for the development of ACLF after proper injury and response. © 2016 by Thieme Medical Publishers, Inc.