The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) identifies 10 separate classes of substances related to significant substance abuse concerns. Of the 10 separate substance classes, four have more clearly documented patterns of pathophysiological sequelae and demonstrated impact on cognitive functioning. These substance categories include alcohol, inhalants, sedatives/hypnotics/anxiolytics, and stimulants. The remaining six substance clusters include caffeine, cannabis, opioids, hallucinogens, tobacco, and other or unknown substances. This chapter discusses the specific impact of each of these separate classes of drugs and related acquired brain injury on cognitive and emotional functioning. The clinical presentation associated with acquired brain injury related to substance use/misuse is variable. Most importantly, the patient will need to gradually reduce his benzodiazepine use so as not to facilitate “rebound anxiety.” Consideration should be given to anxiolytic medications that are not benzodiazepines, as well as to cognitive behavioral therapy, potentially including interceptive exposure.