The objective of this study was to apply preclinical research of paclitaxel radiosensitization to the treatment of thoracic malignancy. Human lung cancer cell line NCI520 and epidermoid cell line A431 were investigated in vitro for radiosensitizing effects of paclitaxel. Optimal schedule of paclitaxel treatment was applied to a clinical protocol as well as off-protocol treatment of thoracic malignancy. Pulsed paclitaxel with concurrent once-daily radiation was delivered every 48 hours during the week using doses of 15 mg/m2, 20 mg/m2, or 25 mg/m2 in a phase I clinical trial of dose escalation. Preclinical data support the finding that low-dose paclitaxel is sufficient for radiosensitization. Data also support that delaying radiation is better than immediate radiation after drug treatment. Twenty-three patients have enrolled in the phase I clinical trial. Seventeen patients completed treatment (6 at 15 mg/m2; 5 at 20 mg/m2; and 6 at 25 mg/m2). Mean tumor shrinkage at 4 to 6 weeks after therapy was 82%, 84%, and 84% for dose levels I, II, and III, respectively [average primary tumor shrinkage was 83% +/- 8% (95% C.I.)]. Locoregional tumor response rate was 100% [12% (2/17) complete response and 88% (15/17) partial response] with low rates of toxicity. It is concluded that pulsed low-dose paclitaxel and radiation is a very effective and well-tolerated regimen for thoracic malignancy.