Breast cancer is a complex disease with high prevalence in the European Union and world-wide. 75%-80 of the patients have estrogen receptor-positive (ER)-positive tumors and are treated with endocrine therapies. Endocrine therapies, which block ER-driven tumor growth, show high efficacy. Yet, a significant proportion of the patients will eventually relapse with metastatic breast cancer, and the recurrence rates remain almost constant for up to 20 years. MESI-STRAT develops metabolite marker panels measurable in biological fluids to enable patient stratification, resistance monitoring and clinical decision-making throughout endocrine therapy. This is a new concept as breast cancer metabolism is poorly explored for diagnostics and therapy. Upon successful validation in preclinical models, the predictive marker panels and related treatments will be jointly investigated by MESI-STRAT’s clinical and industrial partners. The MESI-STRAT consortium explores the interplay of breast cancer metabolism and oncogenic signaling (MEtabolic SIgnaling) by systems medicine approaches. MESI-STRAT develops new models for knowledge-based STRATification of patients into subgroups with different endocrine therapy resistance mechanisms.