How can we protect healthy subjects from harmful medical interventions? How to avoid interactions and adverse events by too many drugs in polymorbid, elderly patients? There is time for action, as polypharmacy patients have an elevated risk of morbidity, hospitalization, nursing home placement and death. We present validated tools (Beer's list, Priscus list) and strategies (Medication Appropriateness Index, Good Palliative Geriatric Practice) which may also facilitate this duty. Reducing polypharmacy is a challenge, (yet) out of daily routine and has to be performed together with the patient (shared decision making). Underuse and inappropriate medication is an important issue and must be avoided. The potential benefit for patients by reducing polypharmacy is enormous: Less is more!