Hormone responsiveness is a critical determinant of breast cancer progression and management, and the response to endocrine therapy is highly correlated with the estrogen receptor (ER)3 and progesterone receptor (PR) status of tumor cells. Thus, key areas of study in breast cancer are those mechanisms that regulate ER and PR expression in normal and malignant breast tissues. One-third of all breast cancers lack ER and PR; these conditions are associated with less differentiated tumors and poorer clinical outcome. In addition, approximately one-half of ER-positive tumors lack PR protein and patients with this phenotype are less likely to respond to hormonal therapies than those whose tumors express both receptors. Since PR is induced by ER; its presence is a marker of a functional ER. In this review, we will discuss possible mechanisms for loss of ER and PR gene expression, especially structural changes within each gene including deletions, polymorphisms or methylation. Improved understanding of the pathways that lead to loss of ER and/or PR proteins should allow the development of better predictive indicators as well as novel therapeutic approaches to target these hormone-independent cancers.