The maintenance of genome stability is important not only for cell viability, but also for the suppression of neoplastic transformation in higher eukaryotes. It has long been recognised that a common feature of cancer cells is genomic instability [1-3]. Although the so-called three 'Rs' of genome maintenance, DNA replication, recombination and repair, have historically been studied in isolation, a wealth of recent evidence indicates that these processes are intimately interrelated and interdependent [4-9]. In this article, we will focus on challenges to the maintenance of genome integrity that arise during the S-phase of the cell cycle, and the possible roles that RecQ helicases and topoisomerase III play in the maintenance of genome integrity during the process of DNA replication.