In this review, we focus on the discrepant roles of the DNA repair complex ERCC1/XPF in the prevention of cancer and in the resistance of cancer to chemotherapy. ERCC1/XPF is essential for nucleotide excision repair (NER) incising DNA 5′ to the lesion. NER deficiency results in the skin cancer-prone inherited disease xeroderma pigmentosum (XP). The ERCC1/XPF complex is also involved in recombination, double strand break (DSB) and interstrand crosslink (ICL) repair cutting DNA overhangs around a lesion. In telomere maintenance ERCC1/XPF degrades 3′ G-rich overhangs. In some types of cancer, high levels of ERCC1/XPF mRNA and protein correlate with poor overall survival and resistance to platinum-based chemotherapeutic treatments. Therefore, the ERCC1/XPF complex makes an attractive target for prediction of outcome for treatment in cancer patients as well as a novel drug target.