Tobacco use is the largest single cause of preventable mortality and morbidity worldwide and it is strongly associated with a variety of mental illnesses. Smoking is considered as a modifiable risk factor that has a significant impact on physical health, including lung diseases, cardiovascular disease, peptic ulcer disease, reproductive problems, and diminishment of bone minerals. Additionally, smoking is a major global public health issue and mortality is estimated to be around 6 million people per year. The prevalence of smoking in people with mental illness can range from 50 to 85%, and they are much less likely to quit smoking compared to the general population. Nicotine addiction plays a significant role in the maintenance of smoking in people with mental illnesses. Hence, it is important to encourage smoking cessation to reduce the health risk of smoking. In terms of smoking intervention, international guidelines recommend to treat smoking both pharmacological and with behavioral support in mentally ill patients. Furthermore, prevention strategies are also essential to control the harm of smoking at the public and individual levels. This chapter will highlight the effect of smoking and nicotine dependence among people with mental illness and their therapeutic policies to enhance the understanding of prevention and management of tobacco use as well as nicotine dependence.