Drug delivery to the brain poses unique challenges. Specialized anatomic and physiological features of the cerebrovasculature and cerebral tissue fluids result in barriers which significantly restrict delivery of a wide range of possible therapeutic agents. In addition to these normal restrictions to brain drug delivery, pathophysiological features and sequelae of acute brain injury will also impact upon the efficiency of drug delivery. This review is focused on acutely damaged brain that occurs after stroke and trauma. Pathophysiological events that may influence drug delivery include blood-brain barrier disruptions, blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered profiles of gene expression and protein synthesis. Careful consideration of these obstacles will provide a framework for further research into the optimization of drug delivery strategies into damaged brain. Without a rigorous assessment of these issues, it may not be possible to translate our mechanistic understanding of acute brain injury into successful clinical therapies.