Estrogen receptor (ER)-positive breast cancer research is an ideal example of how systems biology can be applied to better understand a specific clinical issue. By integrating vast data sets from tumor-derived expression arrays, genome-wide transcription factor/chromatin interactions, proteomics and computational analyses, we may better understand the concept of breast cancer development, heterogeneity, and its treatment. Resistance to endocrine treatment, such as anti-estrogens, often occurs and systems biology may prove to be a valuable asset in tailoring treatment for each patient. In such a multidisciplinary setup, it is essential to try and connect these massive data streams with the known pathological background and cell biology. In this review, we describe the current status of such studies and the challenges that are to be met in order to fully understand the concept of anti-estrogen resistance from a holistic perspective.