The introduction of the so-called "targeted therapies", particularly those drugs that inhibit the activity of tyrosine kinases, has represented a remarkable progress in the treatment of cancer. Although these drugs improve survival rates in cancer, significant cardiotoxicity, manifesting as left vertricular dysfunction and/or heart failure, has emerged. The ErbB receptor tyrosine kinases are being pursued as therapeutic targets because of their important roles in normal physiology and in cancer. Besides the fact that the ErbB receptors are indispensable during development and in normal adult physiology, epidermal growth factor (EGFR) and ErbB2 in particular have been implicated in the development of many human cancers. This review focuses on the rationale for targeting members of ErbB receptor family and numerous agents that are in use for inhibiting the pathway. We summarize the current knowledge on the physiological role of ErbB signaling in the ventricle and on structural aspects of ErbB receptor activation in cancer and cardiac cells. We examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of ErbB inhibitors, which can influence the design of future anticancer therapies.