Anxiety sensitivity (AS)— fear of anxiety symptoms and their potential negative consequences—has been implicated in the development of substance use problems and motivation to use substances for coping with distress, though the AS components (physical, cognitive, and social concerns) have not been studied extensively in relation to alcohol- and cannabis-related variables. In a cross-sectional design, self-report measures of AS and alcohol and cannabis use, motives, and problems were administered to 364 treatment-seeking cigarette smokers with a history of alcohol and cannabis use. In both adjusted and unadjusted analyses, linear regression models indicated that AS cognitive concerns are related to cannabis-use conformity motives, alcohol-use coping motives, and alcohol problems; AS physical and cognitive concerns are related to greater cannabis problems specifically in males; and AS social concerns are associated with greater social, coping, enhancement, and conformity drinking motives. AS cognitive and physical concerns were also related to greater alcohol and cannabis problems, respectively, in subsamples limited to 214 current alcohol users and 170 current cannabis users. Together with prior work, current findings suggest that it may be beneficial to focus more on addressing AS cognitive concerns in individuals with tobacco-alcohol problem comorbidity, whereas it may be beneficial to focus on addressing both AS physical and cognitive concerns in males with tobacco-cannabis problem comorbidity. In addition, cigarette smokers high in AS social concerns may benefit from relaxation training to lessen their social anxiety as well as behavioral activation to enhance their positive affect.