Nearly half of the U.S. adult population will have a major mental illness during their lifetimes. At any point in time, almost a fifth of all American adults have a serious mental illness (SMI). Too many in our society do not understand mental illnesses, placing the blame for the illness on those with the illness, resulting in isolation, marginalization, or incarceration of individuals with SMIs. They may experience stigma, inadequate and delayed health and mental health care, and major socioeconomic disadvantages. They may struggle with activities of daily living, lose many of their resources, and spiral down into poverty. The disadvantages and decreased ability to function experienced by individuals with SMIs lead to increased unhealthy behaviors, reduced participation in wellness-related activities, and premature morbidity and mortality. The general and physical health of individuals with SMIs poses greater challenges from both practice and research standpoints. However, health educators are poised uniquely to provide health promotion programs, conduct research, and advocate for the health and well-being of individuals with SMIs. In this review, we summarize the challenges and opportunities for health promotion in individuals with SMIs.