Steroid hormones, in particular estrogen and progesterone, play important roles in normal and neoplastic breast development. Alterations in both estrogen signaling and progesterone signaling likely occur during breast tumorigenesis and breast cancer progression. This is demonstrated by alteration of estrogen (ER) and progesterone (PR) receptor isoform expression as well as other factors such as coregulators, that can affect the activity, directly or indirectly, of in particular ER signal transduction pathways during breast tumorigenesis and breast cancer progression. A commonly emerging theme is the marked alteration of estrogen action that occurs during these processes. Since targeting ER signaling previously was successful, a better knowledge of all the molecular players involved in regulating estrogen signaling pathways and identifying changes that occur in vivo, seems critical to further exploit this previously successful approach and identify new targets for prevention and treatment of human breast cancer.