For more than four decades, modulation of estrogen receptor activity with antiestrogens has been a successful strategy for the treatment of breast cancer. However, therapeutic resistance limits this approach. Patients whose tumors lack estrogen receptors are not candidates for antiestrogens. Furthermore, roughly half that do express estrogen receptors fail to respond. Together, these tumors are considered to be de novo resistant. For those with tumors that do respond, most will eventually acquire resistance. As such, the underlying mechanisms of both de novo and acquired resistance have been the subject of considerable research, so that new therapeutic targets might be discovered and developed. From this work, epigenetic regulation of gene expression has emerged as a major contributor to both forms of resistance. In this article, we present our current understanding of the mechanisms that contribute to antiestrogen resistance, focusing on epigenetic regulation, and examine the approaches being used that target epigenetic machinery to overcome resistance both in the laboratory and in the clinic.