Objective: In recent years there has been an increasing body of literature concerning the substantial impact that substance use disorders, mental health disorders and other medical conditions (comorbidity) have on each other and the increased burden on health services. This is a particular problem for nurses and midwives who are regularly ‘the first point of contact’ for this comorbid population. Many of these professionals (including those specialising in drug and alcohol and mental health) have been ill-prepared and supported in understanding, assessing and recognising comorbidity despite their pivotal role in offering early intervention, timely treatment/referral and recovery support. Part of the problem is that while the amount of literature around comorbidity has increased, there has been a conspicuous dearth of translation of this material into practical guidelines. Method: This paper discusses new Clinical Comorbidity Guidelines for Nurses and Midwives. These have been specifically designed to boost the capacity of these professionals to respond more effectively to young people and adults with coexisting drug and mental health problems, and other medical conditions, who present to diverse health services with diagnoses such as alcohol/drug dependence, depression, psychosis, anxiety disorders, PTSD and associated medical conditions. Content in this resource includes integrated Comorbidity triage, assessment, intervention planning and delivery, collaborative team work, and referral. Also described are the individual and organisational factors that impede the provision of ‘best care’ to this client group, and strategies to remove these barriers. Conclusion: The Guidelines, which are one component of a broader nursing workforce development strategy, have been drawn from the comorbidity literature, clinical expert advice and national policy. This potentially national innovation has been a direct response to requests from the general and specialist nurses and midwives represented on the Alcohol, Tobacco and Other Drug Nursing & Midwifery State-wide Action Group, in South Australia.