The emergence of chemotherapy has dramatically improved both quality of life and survival in patients with small cell lung cancer (SCLC). Nonetheless, achieving long-term survival in SCLC patients has been a problem. Early studies of combination chemotherapy with cyclophosphamide/doxorubicin/vincristine (CAV) and cyclophosphamide/methotrexate/lomustine/vincristine (CMCV) reported impressive response rates in patients with SCLC. Ifosfamide, an analogue of cyclophosphamide, has demonstrated single-agent activity against SCLC, achieving overall response rates ranging from 5.6% to 76.5%. Because of this, and because of the agent's proven synergism in combination chemotherapy for recurrent testicular cancer and its relative non-myelosuppressive qualities (compared with cyclophosphamide), the incorporation of ifosfamide into combination chemotherapy for SCLC was rational. The Hoosier Oncology Group reported high response rates with VIP (ifosfamide combined with etoposide/cisplatin) in SCLC patients and proved the superiority of VIP over etoposide/cisplatin in patients with extensive disease. Presently, this group is evaluating the role of chronic oral etoposide as maintenance chemotherapy for patients with extensive SCLC that responds to initial VIP treatment. Salvage treatment with daily oral etoposide has also produced encouraging results, leading the Hoosier Oncology Group to incorporate oral etoposide as part of the VIP regimen (VoIP). It is currently unclear whether combination chemotherapy containing daily oral etoposide will have a major impact on survival. Further trials of combination chemotherapy with newer active agents like paclitaxel and topotecan, as well as with proven single agents like ifosfamide, are clearly warranted to improve the outcome of patients with SCLC.