Novel cancer therapies have focused on specific molecular markers present in malignant tumors. The rationale of targeted therapy relies on the knowledge of molecular mechanisms involved in carcinogenesis and their influence in clinical outcome allied to a more specific and less toxic treatment. Activation of EGF receptor and HER2 is an important factor for initiation and progression of malignancies, including breast cancer where the status of HER2 is an essential step in the diagnostic workup; EGFR overexpression has been associated to the so-called basal-like breast carcinomas, which opens a new avenue for diagnosis and therapeutic approach in these tumors. This review will focus on mechanisms of HER2 and EGF receptor upregulation, the targeted therapies that are currently in use for these receptors, possible combined therapies, as well as the approach for molecular diagnosis from the pathologist's point of view.