Through the use of three scenarios, this paper presents thechallenges for clinical practice guidelines in the 21st century.Such challenges relate to technological developments to improve theefficiency and pace of the development process, to ensure thatclinical practice guidelines are kept up to date, and to facilitateimplementation of guidelines in the clinical setting. To improve andensure the validity of the content of clinical practice guidelines,we need to address the important problem of publication bias, forwhich researchers, granting agencies, industry, and journal editorsshare responsibility. This means insisting on registration of trialsat their inception, and incentives backed up by rules for funding andpeer review publication that would promote behaviors to avoidpublication bias. The more difficult challenges for clinicalpractice guidelines relate to what are referred to as attitudinalfactors. To achieve optimal efficiencies in development andmaintenance of clinical practice guidelines, we need to promotecooperation among various information resource providersinternationally and to stress partnership over leadership. Finally,there needs to be reconciliation of the different stakeholderperspectives of the value and purpose of clinical practice guidelinesso that they are used appropriately as aids to decision making andare not abused as tools for controlling clinical practice.