In this review we discuss current challenges faced by researchers and clinician-scientists in the pursuit of therapeutics to treat hypoxic-ischemic (HI) brain injury in term infants. At present, there is an absence of neuroprotective drugs that are safe and effective for the protection of neonates from neurological sequels after HI. We discuss secondary neurotoxic processes elicited by HI that may be targets for therapeutic interventions with a specific focus on inflammatory mechanisms. Advances in research to unravel these cellular processes and molecular mechanisms that drive injurious processes after HI have traditionally been plagued by conflicting results when assessing different times for intervention, different models for brain injury, and the adult versus neonate brain. We attribute impeded drug development in part to such disparate results and general difficulties to conduct a stringent, comprehensive analysis of candidate drugs prior to clinical trials. It will be imperative to implement changes in the clinic and laboratory in order for future drug initiatives to achieve success. We also provide a brief discussion on the pursuit of anti-inflammatory molecules and monitoring methods that are the focus of current patents and that, in our opinion, may lead to important new developments in the treatment of HI brain injury in newborn infants.