Globally more than 10 million people are held in prisons on any given day, giving an imprisonment rate of 144 per 100,000 population. Clear evidence indicates that the burden of substance use disorders and mental illnesses is much higher among prisoners than among the general population. The co-occurrence of these two conditions is termed dual diagnosis. The high occurrence of multiple disorders is a critical challenge for the prison health system and, regrettably, most prisoners have inadequate access to health services, particularly mental health services while in custody. This chapter explores the prevalence, incidence, and effective treatment of substance use, mental disorders, and dual diagnosis among prison populations around the world. The impact of imprisonment on drug use and mental health is discussed, and gaps in knowledge and practice are highlighted. Recommendations for future approaches to addressing substance use disorders, mental illnesses, and dual diagnoses among prisoners and detainees are explored.