Estrogen hormones play critical roles in the regulation of many tissue functions. The effects of estrogens are primarily mediated by the estrogen receptors (ER) α and β. ERs are ligand-activated transcription factors that regulate a complex array of genomic events that orchestrate cellular growth, differentiation and death. Although many factors contribute to their etiology, estrogens are thought to be the primary agents for the development and/or progression of target tissue malignancies. Many of the current modalities for the treatment of estrogen target tissue malignancies are based on agents with diverse pharmacology that alter or prevent ER functions by acting as estrogen competitors. Although these compounds have been successfully used in clinical settings, the efficacy of treatment shows variability. An increasing body of evidence implicates ERα polymorphisms as one of the contributory factors for differential responses to estrogen competitors. This review aims to highlight the recent findings on polymorphisms of the lately identified ERβ in order to provide a functional perspective with potential pharmacogenomic implications.