Progestins at standard doses have compared favorably with tamoxifen for the front-line treatment of women with metastatic breast cancer. Attempts to further enhance the role of progestins have centered on dosage escalation, based on European data suggesting a dose-response effect. A phase I/II pilot trial at the University of Maryland demonstrated that doses of megestrol acetate up to 1,600 mg/d were well tolerated for prolonged periods. Responses were seen in patients whose disease was refractory to both standard doses of megestrol acetate and to tamoxifen. Different mechanisms of progestin action on breast tumors are theorized at the higher doses, which could account for the dose-response effect. Two large multi-institutional dose comparison trials of megestrol acetate in metastatic breast cancer have been undertaken in the United States. The Piedmont Oncology Association recently reported a significant benefit for megestrol acetate 800 mg/d compared with the standard 160 mg/d in terms of response and disease-free and overall survival. The largest trial is currently ongoing in the Cancer and Leukemia Group B. They are comparing 800 and 1,600 mg/d with standard doses, and results from this study are eagerly anticipated.