As awareness for diagnosing and screening patients for trauma has grown, more effective evidence-based treatments are available to treat post-traumatic stress disorder (PTSD). Despite these gains, several patients are non-responsive to care and research has shifted to determining barriers for cure or improvement. With the advent of modern warfare, the combination of intermittent explosive devices and more robust armor has resulted in service members surviving blasts that historically would have been lethal, resulting in a rise in traumatic brain injuries (TBIs). Post-traumatic stress disorder and TBI are often comorbid and can serve as the aforementioned barriers for cure or improvement for each other if one goes unrecognized. This mini-review will discuss the importance of diagnosing both entities, especially when they are comorbid, by examining how misdiagnosis may interfere with treatment outcomes. Several recent advances in methods to successfully distinguish between the two disorders will be reviewed.© The Author(s) 2020.