There has been much progress in understanding the pathogenesis of hypoxic-ischemic brain injury in the near-term and term infant. Although gaps in our knowledge base persist, advances over the past two decades have led to the development of specific brain oriented therapies directed at critical events contributing to tissue damage. The primary goal of these interventions is to prevent or attenuate neurologic and developmental sequelae of brain injury. Examples of current potential treatments include modest reductions in brain temperature, receptor antagonists of excitatory neurotransmitters, reductions in O2 free radicals, blockade of inflammatory mediators, and inhibition of apoptotic pathways. At present, some of these treatments have sufficient animal data that demonstrate benefit, to justify moving experiments from the laboratory to the clinical arena. Modest hypothermia represents the neuroprotective intervention that has been investigated in the most complete fashion for the newborn, and there are multiple ongoing clinical trials testing its efficacy. This review will address specific challenges that are pertinent to the evaluation of any neuroprotective therapy implemented shortly after birth. Specific issues to be covered include the therapeutic window, establishing a diagnosis of hypoxic-ischemic encephalopathy, patient selection, characteristics of an effective therapy, safety considerations, appropriate outcome variables, and sample size considerations. Since clinical trials of brain hypothermia are in progress, many of these issues will be addressed from the perspective of this specific intervention.