Combustible tobacco use remains the leading cause of premature death and disability in the U.S. But, great progress has been made in reducing cigarette smoking in the U.S.: The prevalence of smoking is at its lowest level ever during the last half century, especially among adolescents. Nicotine and tobacco use are complex behaviors, becoming even more so with the dramatic changes in availability of alternative nicotine delivery systems, and the potential for dual and poly-product use, as well as for reduced harm products. This chapter reviews patterns of tobacco and nicotine use; the development of nicotine dependence; current conceptualizations of tobacco use behavior that incorporate the intersecting influences of multiple factors across environmental, policy, psychological, and social levels; and discusses implications for future interventions to reduce the harm from combustible tobacco use.