Patients, clinicians, payers and policy makers face substantial uncertainties in their respective healthcare decisions as they attempt to achieve maximum value, or the greatest level of benefit possible at a given cost. Uncertainties largely come from incomplete information at the time that decisions must be made. This is true in all areas of medicine because evidence from clinical trials is often incongruent with real-world patient care. This article highlights key uncertainties around the (comparative) benefits and harms of medical technologies. Initiatives and strategies such as comparative effectiveness research and coverage with evidence development may help to generate reliable and relevant evidence for decisions on coverage and treatment. These efforts could result in better decisions that improve patient outcomes and better use of scarce medical resources.