Optimal identification of the risk of developing cardiotoxicity upon trastuzumab (TZM) treatment appears necessary as this risk may impair treatment compliance and compromise long-term recovery. To better understand and predict cardiac toxicity, the molecular mechanisms underlying this phenomenon need to be known. HER2 is present at the cell surface of cardiomyocytes. Neuregulin is produced by cardiac endothelial cells and binds to HER4, thus leading to dimerization with HER2 and subsequent cell signaling necessary for normal cardiac function. Decreasing HER2 activity has a major impact on cardiomyocyte function. However, the precise molecular mechanisms responsible for TZM-induced cardiac dysfunction are still unclear. This mini-review aims to summarize genetic, pharmacological and medical data helping to identify mechanisms that could explain cardiotoxicity. Of potential interest, these mechanisms highlight the importance of HER2 genetic polymorphism (Val655Ile) in the identification of patients at risk of developing TZM-induced cardiac effects.