Steffi Oesterreich and colleagues report that the homeobox gene HOXC10 is hypermethylated at a CpG island shore in aromatase inhibitor (AI)-resistant breast tumors (Sci. Transl. Med. 6, 229ra41, 2014). The authors profiled the methylomes of two cell line models of AI-resistant breast cancer and identified 72 hypermethylated regions enriched for developmental genes, including HOXC10. DNA and histone methylation at an estrogen-responsive element in the distal promoter region of HOXC10, near an extensive CpG island, was associated with transcriptional repression. In cell lines, HOXC10 silencing led to an increase in cell growth, proliferation and motility and to a decrease in apoptosis. In mouse xenograft models, cell line–derived tumors that developed resistance to estrogen deprivation showed hypermethylation at HOXC10 compared to estrogen-stimulated controls. Finally, the authors showed that HOXC10 expression levels were lower in a small set of patient-derived tumors that recurred after AI therapy than in matched primary tumors.