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The article reviews the challenges facing cardiovascular disease (CVD) guidelines committees.Clinical trials in high-risk populations have shown additional CVD event reduction with ezetimibe and proprotein convertase subtilisin–kexin-9 inhibitors. These trials recruit middle-aged secondary prevention populations, whereas increasingly the population at risk of CVD comprises the elderly in primary prevention. Some major guidelines have moved from a lipid-target to a risk-based approach. Some guidelines wish to preserve treatment targets to optimize the risk profile of individual patients as opposed to using population-based approaches. A numbers needed to treat approach has been suggested as a way of prioritizing patients for treatment, while retaining an individual's LDL cholesterol risk. However, the main barrier to implementation of some novel therapies in medicine is not their efficacy or safety but their cost. Health economic approaches that consider both benefits and costs can help guideline committees to define populations mostly likely to benefit.The efficacy and expense of novel treatments is challenging traditional guideline development. Previously guideline committees used only to review clinical efficacy and safety endpoints but now they also have to consider costs to derive recommendations that are practical to implement.