OBJECTIVE To review best practices for early recognition and treatment of conditions resulting in neonatal cholestasis, in order to improve long-term outcomes for affected infants. METHODS Studies, review articles, and meta-analyses pertaining to neonatal-onset cholestasis were sought via electronic databases. Reference lists of studies and review articles supplemented the electronic search. Studies were included if they examined the importance of early diagnosis and intervention for cholestatic jaundice of any cause, and mainly comprised Level II and Level III evidence. RESULTS Review of the relevant literature supports the recommendation that infants with jaundice at 2 weeks of age should be tested for cholestasis by quantifying the direct reacting bilirubin levels in their blood. Subsequent rapid investigation using a diagnostic algorithm enables early diagnosis of the specific cause and facilitates timely intervention for conditions whose outcomes are improved by early treatment. CONCLUSIONS Universal screening for neonatal cholestasis might help with early identification of cases and improve outcomes, although further study is required in the North American setting.