Given recent developments in the United States, where professional clinical societies have attempted to define “value” and consider it in their deliberations about appropriate care, this thematic article describes those recent specialty society efforts in the United States in cardiology and oncology and the multispecialty efforts in the United Kingdom for over 10 years. Despite our high levels of health spendin , and our field’s long and consistent approach to the basic tools of cost-effectiveness analysis (CEA), US private and public payers are not routinely or explicitly using CEAs in their reimbursement decisions. This is a puzzle that raises the following question: Why does the United States have so many skilled pharmacoeconomic practitioners and produce so many CEAs given this apparent lack of interest and trust? There are multiple reasons, but the lack of incentives to use the information certainly matters. This article identifies and discusses a number of key issues and challenges for incorporating CEA into US clinical guidelines development: potential bias in manufacturer-sponsored CEAs, the role of societal perspective, payer-subscriber and physician-patient agency relationships, the need for disease area CEA studies and modeling, patient heterogeneity, investigators’ conflicts of interest, assessing the quality of economic studies, and aggregation of information using multicriteria decision analysis. These developments suggest that the application of CEA in health care decision making in the United States is evolving and may be approaching a tipping point. With increasing pressures on drug prices, perhaps reflecting challenges to industry sustainability, payers, providers, and patients are looking for value for money. CEA should be an important part of this process.