Ifosfamide is an alkylating agent that has demonstrated efficacy in the treatment of several malignancies. Preclinical data also support non-cross-reactivity between cyclophosphamide and ifosfamide in several cell lines. These data suggest that ifosfamide may be highly effective in the salvage setting for breast cancer patients who have received previous treatment with cyclophosphamide. Unfortunately, the available data on ifosfamide use in advanced disease are derived from poorly designed studies that evaluated various patient populations and dosing schedules. This review examines the efficacy of ifosfamide in salvage therapy for breast cancer and emphasizes the need to determine the optimal dosing schedule for ifosfamide used as a single agent or in combination chemotherapy for advanced breast cancer.