Fetal alcohol spectrum disorders (FASDs) are conditions caused by prenatal alcohol exposure in amounts sufficient to cause permanent deficits in brain functioning. Extent of damage largely depends on timing, dose, frequency, and pattern of exposure. Timing is especially important because prenatal alcohol exposure during critical periods of gestation can affect brain development in ways that produce varying patterns of neurocognitive deficits and associated adaptive impairments. This article describes some of the more serious neurophysiological and neuropsychological sequelae of prenatal alcohol exposure that contribute to increased risk for substance abuse problems among people with an FASD. We discuss the unique interface between pharmacological treatment and FASD, noting that failure to consider the possibility of FASD in treatment planning may result in treatment failure and/or relapse. Finally, we present a clinical case example and recommend service accommodations to address some of the impairments in FASD that limit substance abuse treatment success.