Low income and low educational attainment are among the strongest predictors of both smoking prevalence and lapse (i.e., return) to smoking after cessation attempts. Treatment refinement is limited by inadequate knowledge of the specific lapse- or relapse-relevant vulnerabilities characteristic of populations that should be the target of treatment. In the context of a randomized clinical trial design, we describe an experimental medicine approach for evaluating the role of 2 specific lapse-relevant targets relative to the higher stress characteristic of low-socioeconomic contexts: low distress tolerance and low working memory capacity. Furthermore, we use an innovative approach for understanding risk of smoking lapse in smokers undergoing a quit attempt to examine candidate mechanistic targets assessed not only during nicotine use, but also during the conditions smokers will face upon a cessation attempt-during stressful nicotine-deprivation windows. This study is designed to show the incremental value of assessments during deprivation windows, in part because of the way in which specific vulnerabilities are modified by, and interact with, the heightened stress and withdrawal symptoms inherent to nicotine-deprivation states. Specifically, the study is designed to evaluate whether a novel mindfulness intervention (mindfulness combined with interoceptive exposure) can improve upon existing mindfulness interventions and extend therapeutic gains to the modification of mechanistic targets assessed in high-stress or negative affectivity contexts. The overall goal is to validate mechanistic targets and associated interventions for the purpose of expanding treatment options for at-risk smokers. (PsycInfo Database Record (c) 2020 APA, all rights reserved).