In recent studies, epothilone B was shown to have a cytotoxic and radiosensitizing effect on cells. The aim of our investigation was to explain this impact by examining the mode of action of epothilone B on FaDu and A549 tumor cells. Flow cytometry was used for cell cycle distribution and for the evaluation of apoptosis. Metabolic activity was studied by proliferation assay. Influence on nuclei morphology was investigated by DNA-staining. We showed that epothilone B-induced G2/M accumulation is the main rationale for drug-induced radiosensitivity. The cytotoxic effect resulted in apoptotic cell death, decreased metabolic activity, and formation of multinucleated cells.