Oral isotretinoin is a non-aromatic oral retinoid that is highly effective for the treatment of severe inflammatory acne vulgaris that is refractory and/or prone to scarring, and has also been used successfully to treat several other disorders in selected cases. Since its introduction into the United States marketplace in 1982, it has been well recognized that cutaneous side effects characterized by xerotic and desquamative changes are very common, and appear to be related to epidermal dyscohesion, and to some extent the sebosuppressive effects of the drug. Additionally, increased susceptibility to staphylococcal colonization has also been observed. The epidermal barrier impairments that have been associated with oral isotretinoin are reviewed in this article along with clinical implications. Strategies to mitigate the altered effects of epidermal barrier functions are reviewed including the importance of topical barrier repair therapy.