The advances in vectors and molecular tools for genetic manipulation are revealing the potential of gene therapy in the clinic. Apart from immunotherapy approaches for cancer, monogenic diseases are currently the primary candidates for this discipline. However, specific characteristics of each condition determine the chances of success with current gene therapy technologies. Cerebrotendinous xanthomatosis (CTX) is caused by biallelic pathogenic variants in the CYP27A1 gene. It encodes the sterol 27-hydroxylase enzyme (531 amino acids), which is involved in bile acid synthesis from cholesterol. The relatively small size of the coding sequence and its primary role in the liver make CTX a good candidate for gene supplementation approaches based on adeno-associated vectors targeting hepatocytes (AAVs). A pre-clinical proof of concept study in mice suggests that metabolic correction may be possible using clinically feasible doses of the prototypic vector. In contrast with the standard chenodeoxycholic acid (CDCA) treatment, CYP27A1 gene supplementation not only reduced plasma levels of cholestanol but also restored the whole bile acid profile in mice after a single intravenous administration. Clinical trials are needed to validate these results in humans. Coupled with early diagnosis, gene therapy could transform the current management of CTX and improve the quality of life of patients in the near future.