Oral isotretinoin, available in the United States for four decades, has been used for the treatment of recalcitrant nodular and deep inflammatory acne vulgaris. This drug revolutionized the management of patients affected by severe inflammatory disease due to its ability to markedly induce acne clearance coupled with prolonged durations of remission after completion of a course of therapy, usually over approximately five months. Over time, it has become recognized that prolonged remission correlates with achieving a threshold cumulative exposure range of approximately 120 to 150 mg/kg of oral isotretinoin. Lesser exposures have demonstrated a higher risk of earlier recurrence of acne vulgaris and a greater likelihood that the patient will require retreatment. As the oral bioavailability of oral isotretinoin is variable, and highly dependent on administration with food, it is very conceivable that earlier relapse may occur if patients have often ingested oral isotretinoin on an empty stomach, thus leading to lesser actual cumulative drug exposure despite the daily dose administered. This article provides an overview on the dosing of oral isotretinoin, reported data on factors that influence relapse after oral isotretinoin therapy, and the potential impact of coadministration with food.