DNA replication begins with DNA polymerase III creating a replication fork that divides the dsDNA into leading and lagging strands. This fork can stall if the polymerase III holoenzyme encounters a physical obstruction such as DNA regulatory structures, another polymerase holoenzyme, or a mutation in one or both strands. Molecular sensors detect the stall and activate a second set of polymerases, causing the mutation to be bypassed and either corrected or incorporated into the daughter strands—potentially resulting in neurodegenerative disease or in cancer. Recent identification of many of the DNA polymerases involved in translesion synthesis (TLS) has helped shed new light on the molecular mechanisms of mutagenesis, and in the May 23 Science, Vincent Pagés and Robert Fuchs at the Centre National de la Recherche Scientifique Cancerogenese et Mutagenese Moleculaire et Structurale further elucidate the mechanism of action of TLS polymerases (Science, 300:1300-1303, May 23, 2003).