The introduction of trastuzumab into clinical practice changed the natural course of HER2-positive breast cancer. Currently, treatment with trastuzumab represents the standard of care for HER2-positive breast cancer and this treatment has been approved in the adjuvant, neoadjuvant, and metastatic settings. Besides trastuzumab, two other anti-HER2 agents-lapatinib and pertuzumab-have been approved for the treatment of HER2-positive advanced breast cancer. Strong biologic data support the concept of dual HER2 blockade, with different anti-HER2 agents demonstrating complementary mechanisms of action. Several neoadjuvant and metastatic studies performed in HER2-positive breast cancer using dual HER2 blockade have been proven to outperform anti-HER2 monotherapies. These dual combinations of agents represent a promising therapeutic strategy that is now reaching clinical practice. In this review we describe the results of studies utilizing dual blockade in patients with HER2-positive breast cancer.