In 1993, evidence-informed health care was in its infancy. The term “evidence-based medicine” had recently been coined at McMaster University, the Institute of Medicine had published an influential report on developing clinical guidelines, and about 500 systematic reviews were indexed in MEDLINE annually. Against this backdrop, 77 people from 11 countries attended the first Cochrane Colloquium in Oxford and agreed to establish The Cochrane Collaboration, an independent, not-for-profit global organization. Its goal is to help individuals make well-informed decisions about health care by preparing, maintaining and promoting the accessibility of systematic reviews of the effects of health care interventions. The 21st Cochrane Colloquium begins on Sept. 19 in Québec City, Quebec, and will celebrate 20 years of the collaboration. Here we discuss the collaboration’s progress and identify key challenges and opportunities for its future.