Liver disease is an important cause of morbidity and mortality in patients with sickle cell disease (SCD). Despite this, the natural history of liver disease is not well characterized and the evidence basis for specific therapeutic intervention is not robust. The spectrum of clinical liver disease encountered includes asymptomatic abnormalities of liver function; acute deteriorations in liver function, sometimes with a dramatic clinical phenotype; and decompensated chronic liver disease. In this paper, the pathophysiology and clinical presentation of patients with acute and chronic liver disease will be outlined. Advice will be given regarding initial assessment and investigation. The evidence for specific medical and surgical interventions will be reviewed, and management recommendations made for each specific clinical presentation. The potential role for liver transplantation will be considered in detail.