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Although mutagens can attack DNA at any time, at least one round of replication is required before damage becomes a fixed mutation. DNA replication therefore plays an important role in mutagenesis, yet little is known about how replication and various mutagenic mechanisms interact. Here, we present the first pan-cancer analysis of the relationship between mutagenic mechanisms, represented by their sequence signatures1, and DNA replication. Using whole-genome sequencing data from 3056 patients spanning 19 cancer types, we observe a significant impact of replication on 22 out of 29 detected mutational signatures. Association with replication timing and asymmetry around replication origins shed new light on several mutagenic processes, such as suggesting that oxidative damage to the nucleotide pool substantially contributes to the mutational landscape of esophageal adenocarcinoma. Together, our results indicate an involvement of DNA replication and the associated damage repair in most mutagenic processes.