Brain imaging plays a key role in the assessment of traumatic brain injury. In this review, we present our perspectives on the use of computed tomography (CT), conventional magnetic resonance imaging (MRI), and newer advanced modalities such as diffusion tensor imaging. Specifically, we address assessment for immediately life-threatening intracranial lesions (noncontrast head CT), assessment of progression of intracranial lesions (noncontrast head CT), documenting intracranial abnormalities for medicolegal reasons (conventional MRI with blood-sensitive sequences), presurgical planning for post-traumatic epilepsy (high spatial resolution conventional MRI), early prognostic decision making (conventional MRI with diffusion-weighted imaging), prognostic assessment for rehabilitative planning (conventional MRI and possibly diffusion tensor imaging in the future), stratification of subjects and pharmacodynamic tracking of targeted therapies in clinical trials (specific MRI sequences or positron emission tomography (PET) ligands, e.g., diffusion tensor imaging for traumatic axonal injury). We would like to emphasize that all of these methods, especially the newer research approaches, require careful radiologic-pathologic validation for optimal interpretation. We have taken this approach in a mouse model of pericontusional traumatic axonal injury. We found that the extent of reduction in the diffusion tensor imaging parameter relative anisotropy directly correlated with the number of amyloid precursor protein (APP)-stained axonal varicosities (r2=0.81, p<0.0001, n=20 injured mice). Interestingly, however, the least severe contusional injuries did not result in APP-stained axonal varicosities, but did cause reduction in relative anisotropy. Clearly, both the imaging assessments and the pathologic assessments will require iterative refinement.