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Objective: Australian Indigenous peoples in remote and rural settings continue to have limited access to treatment for mental illness. Comorbid disorders complicate presentations in primary care where Indigenous youths and perinatal women are at particular risk. Despite this high comorbidity there are few examples of successful models of integrated treatment. This paper outlines these challenges and provides recommendations for practice that derive from recent developments in the Northern Territory. Conclusions: There is a strong need to develop evidence for the effectiveness of integrated and culturally informed individual and service level interventions. We describe the Best practice in Early intervention Assessment and Treatment of depression and substance misuse study which seeks to address this need. [ABSTRACT FROM AUTHOR]