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Acne is a multifactorial disorder, very common among young people, and a frequent reason for Dermatology consultation. When moderate-to-severe acne is not responsive to conventional treatments, oral isotretinoin is a very effective solution. However, there are cases in which this treatment too fails to produce the expected result. In this case, an 18-year-old male patient with acne, unresponsive to traditional acne therapies, experienced only a partial benefit from oral isotretinoin. Endocrinology consultation and hormonal work-up revealed androgen metabolism anomalies suggestive of a non-classical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. In this case report, the authors discuss when to suspect, how to diagnose, and how to manage similar cases.