While sparsely reported in the literature, Wilms tumor may differentiate into more mature mesenchymal tissue types, such as skeletal muscle, following chemotherapy. The frequency of this event is unknown. Chemotherapy and radiation may induce cytodifferentiation of Wilms tumor cells or select for the survival of less mitotically active cells. In follow-up biopsies, the presence of rhabdomyomatous differentiation can confound the histologic diagnosis. Furthermore, these differentiated tumors appear to be more resistant to chemotherapy, thus biopsy and positron emission tomography scans following chemotherapy and radiation may prevent unnecessary treatment. We report an unusual case of Wilms tumor in a 21- year-old man with rhabdomyomatous differentiation of pulmonary metastases after chemotherapy, which presented a challenge during frozen section diagnosis.