The estrogen receptor (ER) pathway plays a pivotal role in breast cancer development and progression. Endocrine therapy to block the ER pathway is highly effective, but its usefulness is limited by common intrinsic and acquired resistance. Multiple mechanisms responsible for endocrine resistance have been proposed and include deregulation of various components of the ER pathway itself, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways that can provide tumors with alternative proliferative and survival stimuli. Among these, increased expression or signaling of growth factor receptor pathways, especially the EGFR/HER2 pathway, has been associated with both experimental and clinical endocrine therapy resistance. New treatment combinations targeting both ER and growth factor receptor signaling to block the crosstalk between these pathways and eliminate escape routes have been proven highly effective in preclinical models. Results of recent clinical studies, while partly supporting this approach, also highlight the need to better identify a priori the patients whose tumors are most likely to benefit from these specific cotargeting strategies.