Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) is rapidly enabling the comprehensive characterization of genome-wide transcription factor-binding sites, thus defining the cistrome (cis-acting DNA targets of a trans-acting factor). Estrogen receptor (ER) ChIP-seq studies have been performed mainly in cell lines, but Ross-Innes and colleagues have now completed the first such study in clinical breast cancer samples. The study aimed at determining the dynamics of ER binding and differences between more and less aggressive primary breast tumors and metastases. The authors found that ER bound to DNA in both aggressive and drug-resistant tumors but to different sites and with different affinities. Given previous findings from cell lines, FoxA1 appears to play a critical role in this reprogramming of ER binding.