In 2007, we initiated a research program to examine the potential use of advanced glycation end-product (AGE) breakers in heart failure. We and others showed that AGEs are end-products formed by oxidative and non-oxidative reactions between sugars and proteins. AGEs form cross-links with long-living tissue proteins, which cause them to accumulate in the body over time. AGEs can bind to the AGE receptor (RAGE) and thereby induce cardiovascular dysfunction. In several papers, we demonstrated that AGEs were related to the severity of heart failure, and were related to clinical outcome in these patients. This resulted in the design and execution of a phase II randomized controlled clinical trial on the effect of the AGE-breaker alagebrium on exercise capacity and clinical outcome in patients with systolic heart failure. We are currently involved in a second phase II randomized controlled clinical trial with another AGE-breaker, TRC4186, specifically aimed at patients with diabetes and heart failure. These studies may lead to larger phase III trials and the potential use of AGE-breakers in heart failure.