The genetic complexity of cancer has posed a formidable challenge to devising successful therapeutic treatments. Tumor resistance to cytotoxic chemotherapy drugs and radiation which induce DNA damage has limited their effectiveness. Targeting the DNA damage response is a strategy for combating cancer. The prospect for success of chemotherapy treatment may be improved by the selective inactivation of a DNA repair pathway. A key class of proteins involved in various DNA repair pathways is comprised of energydriven nucleic acid unwinding enzymes known as helicases. DNA helicases have been either implicated or have proposed roles in nucleotide excision repair, mismatch repair, base excision repair, double strand break repair, and most recently cross-link repair. In addition to DNA repair, helicases have been implicated in the cellular processes of replication, recombination, transcription, and RNA stability/processing. The emerging evidence indicates that helicases have vital roles in pathways necessary for the maintenance of genomic stability. In support of this, a growing number of human genetic disorders are attributed to mutations in helicase genes. Because of their essential roles in nucleic acid metabolism, and more specifically the DNA damage response, helicases may be a suitable target of chemotherapy. In this review, we have explored this hypothesis and provided a conceptual framework for combinatorial treatments that might be used for combating cancer by inhibiting helicase function in tumor cells that already have compromised DNA repair and/or DNA damage signaling. This review is focused on helicase pathways, with a special emphasis on DNA cross-link repair and double strand break repair, that impact cancer biology and how cancer cells may be chemosensitized through the impairment of helicase function.