In this chapter, we briefly examine substance misuse and mental health among Aboriginal Australians. We explore a range of issues including current substance use and related harms, social and emotional wellbeing and co-morbidity, and the social determinants of mental health and substance misuse. We examine the range of services that have been developed to address these issues, through the National Drug Strategy’s demand, supply and harm reduction framework. We argue that a multi-systemic strategy is required that addresses issues of cultural security, evidence based practice to enhance treatment outcomes, better service coordination, and attention to the development of the Aboriginal substance misuse and mental health workforce. We reiterate that until the social and structural determinants of good mental health are addressed, the co-morbidity of substance misuse and mental health among Aboriginal Australians will linger.