he area of HER2-positive breast cancer is a rapidly changing field. The use of the humanized monoclonal antibody, trastuzumab, significantly improved the prognosis for patients with HER2-positive breast cancer, however, increasing knowledge regarding mechanisms of resistance to trastuzumab have come to light, prompting research into additional methods to target the HER2 protein. The purpose of this article is to discuss evidence for why continued blockade of the HER2 pathway continues to be important despite progression on trastuzumab, as well as to review additional HER2-targeted therapies and progression in the central nervous system. With the availability of new drugs comes the need to determine the appropriate therapeutic combinations and optimal order in which to deliver these therapies. This review summarizes the practice-changing phase III trials and some supporting phase II data regarding the various targeted HER2 therapies available for patients with advanced HER2-positive breast cancer, proposes order for anti-HER2 therapy in the advanced HER2-positive breast cancer patient, and includes information on future strategies. While other reviews on HER2-targeted therapy are available, this review specifically aims at addressing treatment options after trastuzumab failure in the patient with advanced HER2-positive breast cancer.