Therapeutic strategies targeting VEGF and IGF signaling that are undergoing active clinical development for patients whose disease is resistant to trastuzumab. For VEGF signaling, these include using bevacizumab to block secreted VEGF to bind to its receptors, and the small molecule, pazopanib, which inhibits the kinase activation of VEGFR-1, -2, and -3. The monoclonal antibody cixutumumab, which specifically targets the extracellular domain of IGF-1R, and the small molecular tyrosine kinase inhibitor BMS-754807 are promising treatments for trastuzumab-resistant patients.