This article reviews evidence supporting the need for interventions to promote physical activity among persons with serious mental illness. Principles of designing effective physical activity interventions are discussed along with ways to adapt such interventions for this population. Individuals with serious mental illness are at high risk of chronic diseases associated with sedentary behavior, including diabetes and cardiovascular disease. The effects of lifestyle modification on chronic disease outcomes are large and consistent across multiple studies. Evidence for the psychological benefits for clinical populations comes from two meta-analyses of outcomes of depressed patients that showed that effects of exercise were similar to those of psychotherapeutic interventions. Exercise can also alleviate secondary symptoms such as low self-esteem and social withdrawal. Although structured group programs can be effective for persons with serious mental illness, especially walking programs, lifestyle changes that focus on accumulation of moderate-intensity activity throughout the day may be most appropriate. Research suggests that exercise is well accepted by people with serious mental illness and is often considered one of the most valued components of treatment. Adherence to physical activity interventions appears comparable to that in the general population. Mental health service providers can provide effective, evidence-based physical activity interventions for individuals with serious mental illness.