Endocrine resistance presents a major challenge in the management of estrogen receptor (ER)-positive breast cancer and is an area under intense investigation. Although the underlying mechanism is still poorly understood, many studies point towards the ‘cross-talk’ between ER and growth factor receptor signaling pathways as the key in the development of estrogen-independent growth in breast cancer. This review aims to provide the reader our current understanding of various molecular pathways that mediate endocrine resistance and that are being evaluated as therapeutic targets for ER-positive breast cancer. While most of the agents that target these pathways have only been tested in Phase I or small Phase II trials, some have shown encouraging results. A critical issue that remains is the development of research strategies and clinical trials that take into account the molecular heterogeneity of ER-positive breast cancer.