The National Institute for Health and Care Excellence (NICE) in the United Kingdom initiated its clinical guidelines program in 2001 and more than 200 guidelines have been produced to date. As with most of NICE’s other programs, the clinical guidelines program also must take into account the relative costs and benefits of interventions when deciding whether to recommend them. The three main advantages of the program are that 1) it represents an important collaboration with the medical profession, thereby increasing the likelihood of recommendations being adopted; 2) the guidelines provide an opportunity to review all aspects of the clinical pathway, rather than focusing on only the adoption of a new technology; and 3) the guidelines offer the potential to discuss disinvestment as well as new investment. All the guidelines contain a systematic review of the relevant economic evaluation literature, and the 12 guidelines published from January 1 to August 31, 2015, contain 28 de novo economic analyses. The main challenges encountered in the guidelines program are that 1) there is an inevitable tension in advising on the quality of care that individual patients could expect while recognizing the broader public health objectives of equity, fairness, and efficiency; 2) the impact of economics is sometimes lessened because of the lack of time to conduct de novo analyses; and 3) unlike NICE’s technology appraisal program, the adoption of recommendations is not mandatory for the UK National Health Service.