The poor physical health of people with mental illness is a multifaceted, transdiagnostic, and global problem. People with mental illness have an increased risk of physical disease, as well as reduced access to adequate health care. As a result, physical health disparities are observed across the entire spectrum of mental illnesses in low-income, middle-income, and high-income countries. The high rate of physical comorbidity, which often has poor clinical management, drastically reduces life expectancy for people with mental illness, and also increases the personal, social, and economic burden of mental illness across the lifespan. This Commission summarises advances in understanding on the topic of physical health in people with mental illness, and presents clear directions for health promotion, clinical care, and future research. The wide range and multifactorial nature of physical health disparities across the range of mental health diagnoses generate a vast number of potential considerations. Therefore, rather than attempting to discuss all possible combinations of physical and mental comorbidities individually, the aims of this Commission are to: (1) establish highly pertinent aspects of physical health-related morbidity and mortality that have transdiagnostic applications; (2) highlight the common modifiable factors that drive disparities in physical health; (3) present actions and initiatives for health policy and clinical services to address these issues; and (4) identify promising areas for future research that could identify novel solutions. These aims are addressed across the five parts of the Commission: in Parts 1 and 2 we describe the scope, priorities, and key targets for physical health improvement across multiple mental illnesses; in Parts 3, 4, and 5, we highlight emerging strategies and present recommendations for improving physical health outcomes in people with mental illness.