A review of the steps by which the current adjuvant chemotherapy programs for osteosarcoma (COMPADRI-V) evolved over the past 19 years indicates that among the important concepts incorporated into the program are demonstration of antitumor activity of each component, adequate evaluation of patient tolerance of the treatment regimen, progressive improvement in documented treatment results, and concomitant utilization of pharmacokinetic information. The current program utilizes intensified high-dose methotrexate and Adriamycin courses and preoperative chemotherapy. The regimen has permitted ready amalgamation of limb-salvage programs. The success of these approaches is emphasized by the overall survival rate of 79% at three years for the patients with osteosarcoma treated at M. D. Anderson Hospital.