Breast cancer is the most common cancer in women worldwide. Although various subgroups are defined according to the expression of hormones and ErbB family receptors, it is well known that this disease is more heterogeneous than its classification system suggests. As new effective therapeutic choices are developed and used clinically, resistance to these new agents is also being observed. The most promising new anti-HER therapies are T-DM1 and pertuzumab, which has been evaluated in trastuzumab-resistant patients and also in a first-line setting with trastuzumab. The dual blockage of HER seems to be a favorable approach for these patients; however, the downstream signaling steps can be activated to overcome the tyrosine kinase inhibition. Because tumor cells can adapt themselves by using alternative pathways to maintain proliferation, providing a sufficient treatment approach also requires the consideration of possible escape mechanisms in tumor cells. By inhibiting tyrosine kinases combined with another agent that affects downstream factors of the PI3K/AKT/mTOR pathway, drug resistance in breast cancer can be overcome or delayed. In this chapter, we discuss the new tyrosine kinase inhibitors that inhibit more than only HER-2 and discuss some ongoing clinical trials in this area. In so doing, we hope to provide information for overcoming tyrosine kinase drug resistance and to identify the ideal settings for these treatment choices according to recent data.