The present paper presents a review of the second-line treatment of non-small cell lung cancer (NSCLC) and reports a phase I study of the combination chemotherapy of docetaxel (DOC) and S-1 as second-line chemotherapy. Current options for the second-line treatment of NSCLC include cytotoxic drugs, such as DOC, pemetrexed, and targeted therapies. However, single-agent chemotherapy has shown limited activities. A new treatment approach is needed for this patient population. We hypothesized that combination chemotherapy of DOC and S-1 would be effective through the additive and synergistic activities. We performed a phase I clinical trial of this combination chemotherapy. S-1 was administered orally at a dose of 80 mg/m2 for 14 days, followed by a drug-free interval of a week (one cycle). The starting dose level (level 1) of DOC was set to 40 mg/m2, until a dose of 60 mg/m2 was reached at level 3. Three patients were treated with level 2, in which the dose of DOC was increased up to 50 mg/m2. Two of 3 patients had grade 4 neutropenia, which was determined as dose-limiting toxicity. The dose level of DOC 40 mg/m2 on day 1 in combination with S-1 80 mg/m2 for 14 days of a three week cycle was recommended for a phase II study. Partial response was achieved in 4 of the 9 patients. This combined chemotherapy consisting of S-1 and DOC may prove effective for treating recurrent cases of NSCLC. A phase II study is ongoing.