INTRODUCTION: Melatonin preparations are emerging first-line pharmacotherapy for insomnia in children and adolescents with autism spectrum disorder (ASD), but quality, formulation, consistency, dosing, and limited long-term safety data are of concern. The recent approval of pediatric-appropriate prolonged-release melatonin (Ped-PRM) addresses these aspects. AREAS COVERED: A systematic search of PubMed and web of science for prospective, randomized, and controlled trials (RCTs) of melatonin preparations vs placebo in children and adolescents with ASD and the European public assessment report on Ped-PRM was conducted. EXPERT OPINION: Melatonin is rapidly absorbed and undergoes first pass hepatic metabolism by cytochrome CYP1A2; over 80% is excreted in the urine as 6-sulfatoxymelatonin (inactive). Immediate-release melatonin (IRM) is short-acting (3-4 h), whereas PRM provides therapeutic levels throughout the night. Drugs interacting with CYP1A2 are likely to slow-down melatonin metabolism. High variability in bioavailability among subjects calls for dose optimization. Melatonin was essentially safe for short-term use (up to 3 months). Long-term data available for Ped-PRM demonstrate fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%) with no evidence of effects on height, BMI, or pubertal development, tolerance or withdrawal effects following long-term use of this product. Studies on long-term safety of IRM and oversight of melatonin supplement manufacture are warranted.