Treatment of breast cancer requires a fully integrated multidisciplinary management as well as an ongoing dialogue with laboratory scientists. The growing amount of data generated by randomized clinical trials need to be interpreted by the clinicians and discussed with patients, so that treatment decisions might be better individualized. In early breast cancer, three consensus panels have been developed to help with this task: the Early Breast Cancer Trialists Collaborative Group or Oxford Overview, the NIH Consensus Conference on Adjuvant Therapy for Breast Cancer and the St. Gallen International Consensus Panel on the Treatment of Primary Breast Cancer. Nevertheless, even these panels leave us with a good deal of uncertainty about the optimal adjuvant systemic treatment of the disease, especially when it is classified as "endocrine non-responsive". The two most problematic issues regarding the management of endocrine non-responsive breast cancer are: (1) which fit woman should not be treated, with two major "to treat or not to treat" dilemmas, (a) women above 70 years of age, where available evidence is scant and co-morbid conditions more often come into the equation of benefit/risk, and (b) women who have very small invasive tumours (<1 cm); and (2) what is the optimal chemotherapy regimen (type, doses, schedule, timing and duration). The aim of this review is to examine these controversial issues. Two difficult clinical cases, which are representative of those frequently encountered in daily practice, will also be presented and discussed, with the help of a panel of 48 breast cancer experts from different regions of the world.