Drug-induced liver injury (DILI) is an uncommon but significant cause of liver injury and need for liver transplant. DILI in the setting of chronic liver disease (CLD) is poorly understood. Clinical features of patients presenting with DILI in the setting of CLD are similar to those without CLD with the exception of a higher incidence of diabetes among those with CLD and DILI. Diagnosis of DILI in CLD is difficult because there are no objective biomarkers and current causality assessments have not been studied in this population. Differentiating DILI from exacerbation of underlying liver disease is even more challenging.