Cerebrotendinous xanthomatosis (CTX) is a treatable disease, but several challenges, including the heterogeneity in clinical presentation, make it difficult to recognize. CTX therefore remains severely underdiagnosed and often patients experience a lengthy diagnostic journey. In this chapter, we provide a broad overview of disease prevalence and geographic distribution from the review of prior studies and unpublished work. CTX prevalence varies across different ancestries and geographic locations and is highest in areas where consanguinity is more common. We also provide an updated global geographic map of estimated disease distribution using CYP27A1 variant queries performed by healthcare providers as a proxy for CTX clinical activity. A multi-pronged approach is needed to close the gaps between the progress in our understanding of disease and the implementation of effective screening and diagnostic protocols. The hope is that with an increased disease awareness, accurate prevalence estimates, and the future inclusion of CTX in newborn screening panels, patients could be provided with a timely treatment resulting in improved prognosis with a better quality of life with minimal to no symptoms.