Oral sequelae of high-dose chemotherapy, including conditioning chemotherapy for hematopoietic stem cell transplantation, can lead to significant morbidity including potentially serious systemic infectious complications. These complications reduce the quality of life, are associated with higher treatment and supportive care costs, and can affect overall outcome of cancer therapy. Pretreatment oral assessment and intervention followed by the provision of supportive oral care during and after cancer therapy can reduce at least some of the adverse impact of oral complications. A definitive supportive oral care program is strongly recommended for patients scheduled for high-dose chemotherapeutic regimens. This article reviews recent insights into the pathogenesis of common oral problems in patients treated with high-dose chemotherapy regimens and discusses a multidisciplinary approach to management of these complications.