Recombinant human Apo2L/TRAIL (dulanermin) is based on the ligand for death receptors (DR4 and DR5), which promotes apoptosis. We report a patient with refractory chondrosarcoma who demonstrated a prolonged response to dulanermin, and explore mechanisms of response and resistance. This heavily pretreated patient had progressive metastatic chondrosarcoma to the lung. On dulanermin (8 mg/kg IV on days 1 through 5 in a 21-day cycle) the patient achieved a sustained partial response with only sub-centimeter nodules remaining. After 62 months of dulanermin treatment, progressive disease in the lungs was noted, and the patient underwent a resection that confirmed chondrosarcoma. DR4 was detected (immunohistochemistry) in the patient’s tumor, which may have enabled the response. However, up-regulation of pro-survival proteins, namely, phosphorylated (p)-NF-kappaBp65 (Ser 536), p-STAT3 (Tyr 705), pERK 1/2 (Thr 202/Tyr 204), p-mTOR (Ser 2448), FASN and Bcl-2, was also detected, which may have provided the underlying mechanisms for acquired dulanermin resistance. The patient was restarted on dulanermin and has continued on this treatment for an additional 16 months since surgery (78 months since initiation of treatment), with his most recent CT scans showing no evidence of disease.