Smoking is disproportionately higher among persons with depression (45% versus 22%). Furthermore, smokers with depression may experience more challenges when trying to make and maintain a quit attempt, such as greater negative mood symptoms from withdrawal, higher nicotine dependence, and greater likelihood of relapse, than smokers without depression. Despite the complex relationship between tobacco use and depression, smokers with depression are motivated to quit smoking and should be offered cessation services. Several evidence-based smoking cessation treatments are effective for the general population of smokers. Yet the comparative effectiveness of these strategies in smokers with depression is uncertain. Also, it is uncertain if factors that may facilitate targeted interventions, such as depression status, gender, and treatment sequencing (i.e., concurrent versus sequential) for mood and smoking cessation, differentially impact the effectiveness of smoking cessation interventions.