Critically ill neonates experience high rates of morbidity and mortality. Major diagnostic errors are identified in up to 20% of autopsied neonatal intensive care unit deaths. Neonates with undiagnosed or rare congenital disorders may mimic critically ill neonates with more common acquired conditions. The context of the diagnostic evaluation can introduce unique biases that increase the likelihood of diagnostic error. Herein is presented a framework for understanding diagnostic errors in perinatal medicine, and individual, team, and systems-based solutions for improving diagnosis learned through the implementation and administration of an undiagnosed and rare disease program.