Few studies have evaluated the role of concurrent chemoradiation therapy in the management of locally advanced breast cancer. The availability of radiosensitizing chemotherapeutic agents that are effective in breast cancer and the encouraging results achieved by concurrent chemoradiation in other malignancies have prompted us to investigate this approach. Paclitaxel is a promising agent for use with concurrent radiotherapy because of its single-agent efficacy profile and its radiosensitizing effects. A clinical protocol of preoperative paclitaxel and radiation in locally advanced breast cancer is ongoing at our institution to test feasibility, measure pathologic response at mastectomy, and explore association of pathologic response with molecular tumor markers. Initially, the study was designed to test weekly paclitaxel at a dose of 60 mg/m2 during radiation therapy, delivered 5 days a week at 200 cGy fractions to a total dose of 50 Gy over 5 weeks. Due to severe skin toxicity in the first two patients, the protocol was amended to change the scheduling of paclitaxel to 30 mg/m2 twice weekly and to reduce the radiation to 180 cGy fractions to a total dose of 45 Gy, delivered 5 days a week over 5 weeks. Presently, 13 patients have been accrued; preliminary data indicate good tolerance to twice-weekly paclitaxel, and four of eight evaluable patients have achieved pathologic response (one patient who received the weekly regimen and three who received the twice-weekly regimen). In addition, sequential fine-needle aspirations of palpable breast cancers were obtained in patients enrolled in a parallel study of preoperative single-agent paclitaxel (200 mg/m2 every 2 weeks, for a total of four cycles before breast surgery). Preliminary results suggest that a steep increase in the mitotic index occurs during the first day after paclitaxel administration and plateaus between the second and the third day, then decreases to pretreatment values. The peak apoptotic index occurs at approximately 72 hours after paclitaxel administration and decreases at approximately 98 hours. These initial findings suggest that twice-weekly dosing of paclitaxel may optimize recruitment of cells into the G2/M phase of the cell cycle, the most radiosensitive phase.