Re-replication is a major threat to genome stability. Recently we found that single-strand breaks in the form of nicks may cause localized re-replication by an, until recently, over-looked mechanism. Considering that nicks are estimated to be the most common DNA lesions in eukaryotic cells, DNA replication forks are bound to encounter nicks. Here we will explore the mechanisms by which eukaryotic cells may suppress re-replication when replication forks encounter un-repaired nicks. If not functional, this could be one underlying cause for copy number variations and gross chromosomal rearrangements often found in cancer cells.