In this issue of JAMA, Yawn and colleagues1 publish the much-anticipated National Heart, Lung, and Blood Institute (NHLBI) guideline for the management of sickle cell disease (SCD) in the United States. The last SCD guideline sponsored by the NHLBI was published a decade ago. The challenges associated with developing guidelines for individuals with an uncommon disease are unique and formidable because of the reliance on evidence other than clinical trials, in particular expert opinion. Given the importance of evidence-derived guidelines, particularly for management of an uncommon disease, adherence to rigorous methodology is critical for their credibility. The Institute of Medicine (IOM) published guidelines2 to address the most important components of any guideline that will allow for primary care clinicians, specialists, and payers to have confidence in its content. For the foreseeable future, the recommendations from the IOM represent the criterion standard by which guidelines should be assessed.