Neonatal global or focal hypoxic-ischemic brain injury remains a frequent and devastating condition, with serious long-term sequelae. An important issue in any neonatal clinical trial of neuroprotective agents relates to developing accurate measures of injury severity and also suitable measures of the response to treatment. Advanced magnetic resonance imaging techniques can acquire serial and noninvasive data about brain structure, metabolic activity, and the response to injury or treatment. These imaging methods need validation in appropriate animal models for translational research studies in human newborns. This review describes several approaches that use imaging as well as proton magnetic resonance spectroscopy to assess the severity of ischemic injury (e.g., for possible candidate selection) and for monitoring the progression and evolution of injury over time and as an indicator of recovery or response to treatment. Preliminary data are presented on how imaging can be used after neural stem cell implantation to characterize the migration rate, the magnitude of stem cell proliferation, and their final location. Imaging has the potential to allow monitoring of many dimensions of neuroprotective treatments and can be expected to contribute to efficacy and safety when clinical trials using neural stem cells or other neuroprotective agents become available.