Members of the nuclear receptor superfamily are ligand-regulated transcription factors involved in the control of a broad range of normal physiological and disease processes. The estrogen receptor alpha (ERalpha) is a member of the steriod receptor family, which is part of the nuclear receptor superfamily. ERalpha it is important for many biological processes and plays a key role in the pathogenesis of breast cancer. Gene regulation by ERalpha requires the recruitment of a multitude of transcriptional co-regulators to the promoters of estrogen-responsive genes. There is evidence in support of the involvement of these co-regulators in breast cancer progression. We review the role of steroid receptor co-activator-3 (SRC-3), which is frequently amplified in breast cancer, and its role in breast cancer risk, outcome and response to endocrine therapy in patients with breast cancer.