Combination chemotherapy has been shown to be more effective than single-agent therapy for many types of cancer, but both are known to induce drug resistance in cancer cells. Two major culprits in the development of this drug resistance are nuclear factor-kappaB (NF-kappaB) and the multidrug resistance (MDR) gene. For this reason, chemogene therapy is emerging as a viable alternative to conventional chemotherapy combinations. We have shown that transduction of the E2F-1 gene in melanoma cells markedly increases cell sensitivity to doxorubicin, thereby producing a synergistic effect on melanoma cell apoptosis. Our microarray results show that the NF-kappaB pathway and related genes undergo significant changes after the combined treatment of E2F-1 and doxorubicin. In fact, inactivation of NF-kappaB is associated with melanoma cell apoptosis induced by E2F-1 and doxorubicin, providing a link between the NF-kappaB signaling pathway and the chemosensitivity of melanoma cells after this treatment.