As smoking rates in the general population continue to fall in response to new information and changing social values, the continued high rate of smoking among persons with psychiatric disorders has caught the attention of society at many levels: public health officials, medical and mental health care providers, and concerned family members alike. As a consequence, research studies aimed at quantifying the problem and understanding its cause have increased dramatically over the past several years. The following review first examines epidemiological studies that have revealed a bidirectional causal relationship between tobacco dependence and posttraumatic stress disorder (PTSD), one of several mental health disorders in which tobacco dependence remains prevalent and resistant to intervention. Second, we use a translational neuroscience perspective to discuss possible neurobiological mediators of the relationship between PTSD and tobacco dependence, hoping to spur further human and animal research that will elucidate pathogenetic mechanisms involved and inspire novel treatment interventions. Finally, to enable more effective clinical research in this area, we provide an overview of effective scientific methods for assessing and managing ‘smoking status’ as an experimental variable in clinical research studies of PTSD as well as other mental health disorders.