The HER2+ subtype of breast cancer typically results from amplification of the proto-oncogene ERBB2, that causes overexpression of the mitogenic cell surface receptor kinase HER2. Absent targeted therapies, this subtype is one of the most aggressive and invasive of all the breast cancer subtypes. However, because overexpressed HER2 is often the key oncogenic driver in this subtype, it has been a successful target for clinical agents that inhibit it specifically. Trastuzumab, pertuzumab, T-DM1, and lapatinib, are all FDA approved drugs that have significantly improved progression-free survival in HER2+ patients. Despite this, long term survival benefits have been hampered by de novo or emergent resistance to these targeted agents. While cell-intrinsic secondary mutations that result in drug tolerance have been well studied, the less well understood and remarkably complex cell-extrinsic tumor microenvironment has shown a substantial capacity to cause drug resistance in otherwise drug sensitive tumor cells.