We critically evaluated various design features from 292 animal studies related to perinatal hypoxic-ischemic encephalopathy (HIE). Rodents were the most frequently used animals in HIE research (26%), followed by piglets (23%) and sheep (22%). Asphyxia with or without ischemia was the most predominant method of producing experimental brain damage, but there were significant variations in specific details, particularly regarding the method and duration of brain insult. In 71% (207/292) of studies the CNS outcomes were tested within 24 h of experimental insult and in 29% (85/292) they were tested 24 h or more after the insult. Acute CNS metabolic end-points were assessed in 82-100% of all studies. In 90% of studies the chronological age of the animal was equivalent to that of human term newborn infant. However, in only 23% (67/292) were clinical neurological, developmental or behavioral outcomes evaluated, and in only 26% (76/292) was neuropathology assessed. While no single animal model was found to be ideal for all HIE research, some models were distinctly superior to others, depending upon the specific research question. The fetal sheep, newborn lamb and piglet models are well suited for the study of acute and subacute metabolic and physiologic endpoints, whereas the rodent and primate models could be used for long-term neurological and behavioral outcome experiments as well. We also feel that standardizing the study design features, including an HI insult method that produces consistent and predictable brain damage is urgently needed. Studies in neuro-ethology should explore how well brains of various animals compare with that of the newborn human infant. There is also a need for developing animal models that mimic clinical entities in which long-term neuro-developmental and behavioral outcomes can be assessed.