Selection for endocrine therapy requires the identification of markers that accurately predict response/resistance. In this report, the authors review their published work and abstract results from an unpublished study to illustrate the potential of RNA microarrays from sequential tumor biopsies from patients who were offered neoadjuvant endocrine therapy treatment to identify the molecular signatures associated with tumor sensitivity/resistance. Clinical response was assessed by serial ultrasound measurements in postmenopausal women with large, primary, estrogen receptor-rich breast cancers who received neoadjuvant treatment with letrozole for 3 months. Tumor RNA from biopsies that were taken before and after 14 days of treatment was hybridized on Affymetrix U133A chips to determine expression profiles. Classic estrogen-dependent genes and markers of proliferation were changed with treatment in most tumors but were poorly associated with clinical response (they frequently were changed in letrozole-resistant tumors). Differential expression patterns could be used to identify heterogeneity in clinically resistant tumors. The results indicated that molecular profiling of early changes with letrozole treatment offers the opportunity to distinguish between clinically responsive and nonresponsive tumors and provides important information about the heterogeneity of endocrine resistance. Cancer 2008. © 2007 American Cancer Society.