Cytostatic drugs were developed to target specific molecular pathways shown to drive tumor growth. Although this approach has been very successful in treating cancers, its use is often hindered by off-target toxic effects. An example of this is trastuzumab, which targets the erbB2 kinase receptor. This drug successfully decreases tumor growth but adversely affects cardiac function. This observation led to important studies elucidating the importance of the erbB pathway in cardioprotection and angiogenesis. This review addresses the problem of off-target effects of cytostatic drugs (specifically trastuzumab) and their effect on cardiac function, summarizes the neuregulin-1 (NRG)/erbB signaling pathway, and discusses its importance in cardiac myocytes. It also highlights important findings showing the role of NRG/erbB signaling in microvascular preservation and angiogenesis, with a brief discussion of preclinical and clinical data regarding treatment of cardiovascular disease with NRG.