Epigenetic mechanisms play crucial roles in many processes, including neoplasia, genomic imprinting, gene silencing, differentiation, embryogenesis and X chromosome inactivation. Their relevance in human disease and therapy has grown rapidly with the recent emergence of drugs that target for example DNA methylation or histone acetylation. Epigenetic effects were also recently highlighted by the deciphering of the mechanism of action of steroid hormones and anti-hormones acting through nuclear receptors. In this review, we focus on the epigenetic effects associated with long-term treatment of breast cancer cells with the antiestrogen (AE) tamoxifen, in the context of resistance appearance. We summarize the data obtained with a model cell line developed in our laboratory supporting a role for HP1 proteins in the irreversible inactivation of gene expression by long-term treatment with AE.