Hypoxic-ischemic (HI) brain injury is the most common cause of encephalopathy and seizures in term newborn infants. There is no single, valid test for birth asphyxia leading to HI brain injury, and thus this disorder is often poorly characterized, and the timing and etiology of the injury can be difficult to ascertain. Optimal management of HI brain injury involves prompt resuscitation, careful supportive care including prevention of hyperthermia and hypoglycemia, and treatment of clinical and frequent or prolonged subclinical seizures. Recent evidence suggests that therapeutic hypothermia by selective head or whole-body cooling administered within 6 hours of birth reduces the incidence of death or moderate/severe disability at 12 to 22 months. Hypothermia is a promising new therapy that physicians should consider within the context of a registry or study. Optimal seizure treatment remains controversial because the most widely used drug, phenobarbital, has limited efficacy, and the value of monitoring and treating subclinical seizures is uncertain. There is compelling need for well-designed clinical trials to address treatment of ongoing brain injury in the setting of hypoxia-ischemia and seizures. Emerging evidence from preclinical studies suggests that future therapy for HI brain injury and neonatal encephalopathy will combine novel neuroprotective and anti-seizure agents. Pilot clinical trials of newer anticonvulsants are ongoing and will provide critical information for care of neonatal seizures.