Wars in Afghanistan and Iraq have resulted in thousands of military personnel suffering traumatic brain injury (TBI), including closed-head injuries. Of interest is whether these individuals and other TBI survivors are at increased risk for substance use disorder (SUD). While it has been well established that drug or alcohol intoxication itself increases probability of suffering a TBI in accidents or acts of violence, little is known about whether the brain insult itself increases the likelihood that a previously non-drug-abusing individual would develop SUD. Might TBI survivors be unusually vulnerable to addiction to opiate analgesics compared to other pain patients? Similarly, it is not known if TBI increases the likelihood of relapse among persons with SUD in remission. We highlight challenges in answering these questions, and review neurochemical and behavioral evidence that supports a causal relationship between TBI and SUD. In this review, we conclude that little is known regarding the directionality of TBI increasing drug abuse, and that collaborative research in this area is critically needed.