After the major advances seen in the field of HER2 positive disease, fortunately, we have now also much more treatment options available for estrogen receptor positive HER2 negative advanced breast cancer. The better understanding of the mechanisms of resistance to endocrine therapy has allowed a much more rational treatment approach. Chemotherapy is only the preferred treatment option for patients with extensive symptomatic visceral disease. Almost all of our patients receive now an endocrine therapy based approach for several lines of treatment for advanced breast cancer. As endocrine therapy alone is not highly effective most of our patients are good candidates for combined therapy approaches with targeted agents. In the frst-line setting for advanced disease, the CDK4/6 inhibitors are now the targeted agents of choice because of the excellent safety profle in addition to the rapid and pronounced antitumoral effect. Nevertheless, many questions remain unanswered today. How should we treat specific subgroups of patients such as older patients, patients with some co-morbidities, patients with visceral disease or patients presenting bone only disease? Are biomarkers available to select the most appropriate treatments? Is progression-free survival a valid endpoint of clinical trials or do we need overall survival data? What is the optimal sequence? Should we use the best drugs frst? What should be the next line therapy in this case? During my presentation I will summarize the data available today and give you my personal view concerning these questions.