Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AHA) is a rare and severe disease characterized by autoimmune hemolysis associated with acute liver injury, histologically defined by widespread giant cell transformation. It occurs after the neonatal period, most commonly in the first year of life and uniquely affects pediatric patients. It is still poorly understood and likely underdiagnosed, although in recent years there have been advances in the understanding of its pathogenesis and the liver injury is now hypothesized to be secondary to a humoral immune mechanism. Although no laboratory test specific for the diagnosis currently exists, given its severity, it is fundamental to rule out GCH-AHA when evaluating a patient in the first year of life presenting with AHA and/or with acute liver disease of unknown etiology. While GCH-AHA is progressive in nature as other autoimmune liver disorders, it differs significantly from juvenile autoimmune hepatitis (JAIH) in that a cure can be achieved after several years of intensive treatment in a portion of patients. Conventional first line therapy consist of prednisone/prednisolone combined with azathioprine, however, several immunosuppressive drugs, commonly used in the treatment of JAIH have been tried as second line therapy, including cyclosporine, cyclophosphamide, mycophenolate mofetil, 6-mercaptopurine, calcineurin inhibitors, and sirolimus. Intravenous immunoglobulins have also been used in cases of severe liver dysfunction and/or severe anemia allowing for transitory remission. More recently treatment with B-cell depletion has been attempted in some patients and encouraging results have been reported in refractory cases. Although what constitutes optimal treatment has yet to be determined, the recent progress in the understanding of the pathogenetic mechanisms of GCH-AHA have made positive strides, cautiously pointing toward a hopeful prognosis for some of these patients.