Alagille syndrome (ALGS) is an autosomal dominant multisystemic disease, mostly caused by mutations in the JAG1 gene, involved in the Notch signalling pathway through the JAGGED1 protein. It is characterized by protean manifestations that can affect the liver, heart, skeleton, eyes, face, vasculature, and kidneys. The most common hepatic feature is neonatal cholestasis, caused by bile duct paucity, with jaundice and pruritus; other complications, such as end-stage liver disease and portal hypertension, usually arise in early adulthood. Diagnosis is usually made within the first year of life but may be delayed due to a heterogeneous clinical presentation: nowadays, genetic testing is the main tool, whereas liver biopsy is no longer needed. ALGS should require a multidisciplinary management, given its multisystemic involvement. Choleretic therapy still represents the backbone of ALGS patients with cholestasis, but at present, it does not halt the natural history of the disease: promising innovative therapies are on the pipeline. Surgical options, such as partial external biliary diversion (PEBD) and ileal exclusion, may improve the quality of life (QoL) through pruritus relief without modifying the outcome. Liver transplantation (LT) should be reserved for patients having an impaired quality of life caused by pruritus and cholestasis or end-stage liver disease. It requires careful screening (and treatment) of extrahepatic disorders and is associated with good survival curves.