Tobacco use remains the leading preventable cause of death worldwide. In particular, people with mental illness are disproportionately affected with high smoking prevalence; they account for more than 200,000 of the 520,000 tobacco-attributable deaths in the United States annually and die on average 25 years prematurely. Our review aims to provide an update on smoking in the mentally ill. We review the determinants of tobacco use among smokers with mental illness, presented with regard to the public health HAVE framework of “the host” (e.g., tobacco user characteristics), the “agent” (e.g., nicotine product characteristics), the “vector” (e.g., tobacco industry), and the “environment” (e.g., smoking policies). Furthermore, we identify the significant health harms incurred and opportunities for prevention and intervention within a health care systems and larger health policy perspective. A comprehensive effort is warranted to achieve equity toward the 2025 Healthy People goal of reducing US adult tobacco use to 12%, with attention to all subgroups, including smokers with mental illness.