The concept of Less is More medicine emerged in North America in 2010. It aims to serve as an invitation to recognize the potential risks of overuse of medical care that may result in harm rather than in better health, tackling the erroneous assumption that more care is always better. In response, several medical societies across the world launched quality-driven campaigns ("Choosing Wisely") and published "top-five lists" of low-value medical interventions that should be used to help make wise decisions in each clinical domain, by engaging patients in conversations about unnecessary tests, treatments and procedures. However, barriers and challenges for the implementation of Less is More medicine have been identified in several European countries, where overuse is rooted in the culture and demanded by a society that requests certainty at almost any cost. Patients' high expectations, physician's behavior, lack of monitoring and pernicious financial incentives have all indirect negative consequences for medical overuse. Multiple interventions and quality-measurement efforts are necessary to widely implement Less is More recommendations. These also consist of a top-five list of actions: (1) a novel cultural approach starting from medical graduation courses, up to (2) patient and society education, (3) physician behavior change with data feedback, (4) communication training and (5) policy maker interventions. In contrast with the prevailing maximization of care, the optimization of care promoted by Less is More medicine can be an intellectual challenge but also a real opportunity to promote sustainable medicine. This project will constitute part of the future agenda of the European Federation of Internal Medicine.