Heart failure (HF) and diabetes mellitus (DM) commonly co-exist, with a prevalence of DM of up to 40 % in HF patients. Treatment of DM in patients with HF is challenging since many of the contemporary therapies used for the treatment of DM are either contraindicated in HF or are limited in their use due to the high prevalence of co-morbidities such as significant renal dysfunction. This article presents an overview of the physiology of the incretin system and how it can be targeted therapeutically, highlighting implications for the management of patients with DM and HF. Receptors for the incretin glucagon-like peptide-1 (GLP-1) are expressed throughout the cardiovascular system and the myocardium and are up-regulated in HF. GLP-1 therapy improves cardiac function in animal models of HF through augmented glucose uptake in the myocardium mediated through a p38 MAP kinase pathway. Small clinical studies have shown that GLP-1 improves ejection fraction, reduces BNP levels and enhances functional capacity in patients with chronic HF. A number of randomized controlled trials are currently underway to define the utility of targeting the incretin system in HF patients with DM. Incretin-based therapy may represent a novel therapeutic strategy in the treatment of HF patients with diabetes, in particular for their cardioprotective effects independent of those attributable to tight glycemic control.