Breast cancer is the most prevalent life-threatening cancer in women and the second leading cause of cancer associated deaths. Consequently, optimizing breast cancer therapy to increase cure rates in early stage disease and improve life expectancy and palliation for patients with metastasis is a critical need and major area of research in medical oncology. This article focuses on the development of personalized therapy in breast cancer though the use of targeted therapies and their associated biomarkers. Topics reviewed include the historic advances in targeting the HER2 receptor and the current avenues being studied to circumvent resistance; new developments in the management of triple negative and metastatic breast cancer; and the challenges and pitfalls associated with targeting angiogenesis. Using these as examples, many of the innovations and challenges in the treatment of women with breast cancer are explored.