Controversy continues over which animal model to use as a reflection of human disease states. With respect to perinatal brain disorders, scientists must contend with a disease in evolution. In that regard, the perinatal brain is at risk during a time of extremely rapid development and maturation, involving processes that are required for normal growth. Interfering with these processes, as part of therapeutic intervention must be efficacious and safe. To date, numerous models have provided tremendous information regarding the pathophysiology of brain damage to term and preterm infants. Our challenges will continue to be in identifying those infants at greatest risk for permanent injury, and adapting therapies that provide more benefit than harm. Using animal models to conduct these studies will bring us closer to that goal.