Background: Patients with limited-stage (LS) or extensive-stage (ES) small-cell lung cancer (SCLC) are commonly given platinum-based chemotherapy as first-line treatment. Standard chemotherapy for patients with LS SCLC includes a platinum agent such as cisplatin combined with the non-platinum agent etoposide. The objective of the present systematic review was to investigate the efficacy of adding radiotherapy to chemotherapy in patients with ES SCLC and to determine the appropriate timing, dose, and schedule of chemotherapy or radiation for patients with SCLC. Methods: The MEDLINE and EMBASE databases were searched for randomized controlled trials (RCTS) comparing treatment with radiotherapy plus chemotherapy against treatment with chemotherapy alone in patients with ES SCLC. Identified rcts were also included if they compared various timings, doses, and schedules of treatment for patients with ES SCLC or LS SCLC. Results: Sixty-four RCTSwere included. In patients with LS SCLC, overall survival was greatest with platinum–etoposide compared with other chemotherapy regimens. In patients with ES SCLC, overall survival was greatest with chemotherapy containing platinum–irinotecan than with chemotherapy containing platinum–etoposide (hazard ratio: 0.84; 95% confidence interval: 0.74 to 0.95; p = 0.006). The addition of radiation to chemotherapy for patients with ES SCLC showed mixed results. There was no conclusive evidence that the timing, dose, or schedule of thoracic radiation affected treatment outcomes in SCLC. Conclusions: In patients with LS SCLC, cisplatin–etoposide plus radiotherapy should remain the standard therapy. In patients with ES SCLC, the evidence is insufficient to recommend the addition of radiotherapy to chemotherapy as standard practice to improve overall survival. However, on a case-by-case basis, radiotherapy might be added to reduce local recurrence. The most commonly used chemotherapy is platinum–etoposide; however, platinum–irinotecan can be considered.