Chemotherapy induced acral erythema (CIAE) is an uncommon and dramatic reaction to high-dose chemotherapy. It is characterized by symmetrical, well-demarcated, painful erythema of the palms and soles which may progress to bullae formation and desquamation. Prompt recognition and discrimination from more serious conditions such as graft-vs-host disease or toxic epidermal necrolysis is essential. This paper describes the case of a 12-year-old boy who developed CIAE after high-dose methotrexate treatment and discusses the important clinical, histopathological, and therapeutic features of this condition.