Through the use of three scenarios, this paper presents the challenges for clinical practice guidelines in the 21st century. Such challenges relate to technological developments to improve the efficiency and pace of the development process, to ensure that clinical practice guidelines are kept up to date, and to facilitate implementation of guidelines in the clinical setting. To improve and ensure the validity of the content of clinical practice guidelines, we need to address the important problem of publication bias, for which researchers, granting agencies, industry, and journal editors share responsibility. This means insisting on registration of trials at their inception, and incentives backed up by rules for funding and peer review publication that would promote behaviors to avoid publication bias. The more difficult challenges for clinical practice guidelines relate to what are referred to as attitudinal factors. To achieve optimal efficiencies in development and maintenance of clinical practice guidelines, we need to promote cooperation among various information resource providers internationally and to stress partnership over leadership. Finally, there needs to be reconciliation of the different stakeholder perspectives of the value and purpose of clinical practice guidelines so that they are used appropriately as aids to decision making and are not abused as tools for controlling clinical practice.