Congestive Heart Failure a leading cause of morbidity and mortality is often associated with comorbidities and with it polypharmacy. Improved pathophysiological understanding, the available therapeutics, clinical guidelines and structured programs for comprehensive care have not benefited all clients in the Northern Territory of Australia. The Northern Territory has both a unique geography and demography including a sizeable Indigenous population. Additional factors that can affect heart failure management are prevalent in remote areas and are not well addressed within randomized controlled trials. This review is focused on building a case for widening the therapeutic paradigm for heart failure with comorbidities. We focus on a brief overview of heart failure and its associated comorbidities, the common overlapping physiological processes, the interpretation of the external validity of trial evidence, and finally exploring the available evidence for the important therapies within the guidelines. A need to consider a wider therapeutic paradigm may also have relevance for clients in other health systems.