The RecQ family of DNA helicases consists of specialized DNA unwinding enzymes that promote genomic stability through their participation in a number of cellular processes, including DNA replication, recombination, DNA damage signaling, and DNA repair pathways. Mutations resulting in the inactivation of some but not all members of the RecQ helicase family can lead to human syndromes which are characterized by marked chromosomal instability and an increased predisposition to cancer. An evolutionarily conserved interaction between RecQ helicases and topoisomerase 3s has been established, and this interaction is important in the regulation of recombination and genomic stability. Topoisomerases are critical in the cell because they relieve helical stress that arises when DNA is unwound. Topoisomerases function by breaking and rejoining DNA. By inhibition of the rejoining function, topoisomerase inhibitors are potent chemotherapeutic agents that have been used successfully in the treatment of hematologic malignancies and other cancers. This review discusses the roles of RecQ helicases in genomic stability, the interplay between RecQ helicases and topoisomerase 3s, and current and future prospects for targeting these interactions to develop novel anticancer therapies.