Problematic polypharmacy is a growing challenge. Medication that is intended to improve patients’ health and wellbeing is instead becoming part of the problem. The way we practice medicine has become one of the drivers for the problems. Dealing with the challenge will need us to think differently about how we do clinical care. A 2013 Kings Fund report stated that tackling problematic polypharmacy requires us to actively build a principle of ‘compromise’ in to the way we use medicines. There are implications for how we consult and make decisions with patients, in how we design health practice and systems to support that decision making, and in our understanding of the process of research – how we generate the knowledge that informs practice. This review considers the current state of play in all three areas and identifies some of the work still need to do in order to generate the practice-based evidence needed to tackle this most challenging problem. Finding a way to redesign practice to address problematic polypharmacy could offer a template for tackling other related complex issues facing medical practice such as multimorbidity, chronic pain and complex mental health.