DNA interstrand crosslinks (ICLs) are covalent linkages between two strands of DNA, and their presence interferes with essential metabolic processes such as transcription and replication. These lesions are extremely toxic, and their repair is essential for genome stability and cell survival. In this review, we will discuss how the removal of ICLs requires interplay between multiple genome maintenance pathways and can occur in the absence of replication (replication-independent ICL repair) or during S phase (replication-coupled ICL repair), the latter being the predominant pathway used in mammalian cells. It is now well recognized that translesion DNA synthesis (TLS), especially through the activities of REV1 and DNA polymerase zeta (Polζ), is necessary for both ICL repair pathways operating throughout the cell cycle. Recent studies suggest that the convergence of two replication forks upon an ICL initiates a cascade of events including unhooking of the lesion through the actions of structure-specific endonucleases, thereby creating a DNA double-stranded break (DSB). TLS across the unhooked lesion is necessary for restoring the sister chromatid before homologous recombination repair. Biochemical and genetic studies implicate REV1 and Polζ as being essential for performing lesion bypass across the unhooked crosslink, and this step appears to be important for subsequent events to repair the intermediate DSB. The potential role of Fanconi anemia pathway in the regulation of REV1 and Polζ-dependent TLS and the involvement of additional polymerases, including DNA polymerases kappa, nu, and theta, in the repair of ICLs is also discussed in this review.