Mechanical injury to the blood-brain barrier (BBB) is the underlying mechanism for the most common form of closed head injury - cerebral contusions. In vivo thresholds for mechanical disruption of the BBB were identified with a dual experimental and computational modeling approach. A new experimental model of traumatic brain injury in the rat was developed. Termed dynamic cortical deformation (DCD), the model induces graded injury by applying a dynamic vacuum pulse to the cortex, and is the only model that produces an injury pattern that consists solely of a focal contusion. The purely focal pathology was confirmed with a histological and immunohistochemical analysis of the neuronal, axonal, and glial consequences of DCD. A subsequent experimental study assessed the mechanical response of the cortex and the extent of mechanically-mediated BBB breakdown ten minutes after injury over a range of biofidelic loading conditions. BBB injury was identified by the extravasation of Evans blue-tagged serum albumin (a 60 KD protein), and was statistically dependent on both the magnitude and the duration of the insult vacuum pulse. A three-dimensional finite element analysis of DCD in the rat was performed and validated with in vivo experimental cortical displacement data across the range of loading conditions applied experimentally. The results of the computational study were compared to the experimental data of BBB injury using logistic regression analysis. Four mechanical parameters were investigated as potential mediators of BBB injury - maximum principal logarithmic strain, maximum principal stress, strain energy density, and von Mises stress. While all four measures demonstrated significant logistic regression fits at each of the nine loading conditions, only maximum principal logarithmic strain was statistically invariant across loading. These studies demonstrate that mechanical injury to the BBB is strain-mediated, and that injury occurs at natural strain of 17.2%. Identification of this threshold is a vital step in understanding the circumstances that cause traumatic brain injury and can lead to improved means of injury prevention.