Breast cancer is the most common cancer in females in the UK and has greater severity in patients who overexpress human epidermal growth receptor 2 (HER2) proteins in the breast tissue. Trastuzumab is a humanised monoclonal antibody and is targeted towards blocking the HER2 pathway and effectively reduces the recurrence of breast cancer and associated mortality. However, trastuzumab is also associated with an increased risk of cardiotoxicity which likely results from inhibition of the HER2 pathway. Under normal conditions HER2 pathways help maintain the integrity of the myocardial contractile elements, as well as the coronary vasculature, but trastuzumab inhibits these survival pathways and increases the risk for congestive heart failure (CHF). In the present review, we summarise the pathways that are implicated in the development of CHF in patients receiving trastuzumab. We also highlight the role of trastuzumab-mediated endothelial dysfunction and CHF.