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The mammalian target of rapamycin inhibitors (mTORIs) everolimus and temsirolimus are approved by the US Food and Drug Administration (FDA) for the treatment of various forms of advanced cancer, and the mTORI sirolimus is approved as an immunosuppressive agent for the prophylaxis of organ rejection in patients receiving renal transplants. The oral lesions associated with mTORI toxicity are distinct from the well-documented chemotherapy- and radiotherapy-induced mucositis, but they may often be misdiagnosed by medical oncologists or transplant physicians, potentially resulting in inappropriate management of this complication. mTORI-associated oral mucosal injury appears to be dose related, and its onset is consistently earlier than conventional mucositis associated with chemotherapy or radiation therapy. Although the lesions appear to resolve within approximately 2 weeks and do not seem to recur as severely with subsequent courses of therapy, the reduction in a patient's quality of life as a result of oral pain that affects the intake of nutritional foods should be taken into consideration. We report three cases that illustrate the complexity involved in the early assessment, referral, and appropriate management of mTORI-associated oral mucosal injury. Corticosteroids appear to be very useful in managing and perhaps preventing these lesions, whereas this approach has never shown efficacy in conventional chemotherapy-related mucositis. Early intervention to reduce the mTORI-associated oral mucosal injury is important to diminish the need for dose alterations of mTORIs and, therefore, to improve patient outcomes.