Living cells are continually exposed to DNA-damaging agents that threaten their genomic integrity. Although DNA repair processes rapidly target the damaged DNA for repair, some lesions nevertheless persist and block genome duplication by the cell's replicase. To avoid the deleterious consequence of a stalled replication fork, cells use specialized polymerases to traverse the damage. This process, termed "translesion DNA synthesis" (TLS), affords the cell additional time to repair the damage before the replicase returns to complete genome duplication. In many cases, this damage-tolerance mechanism is error-prone, and cell survival is often associated with an increased risk of mutagenesis and carcinogenesis. Despite being tightly regulated by a variety of transcriptional and posttranslational controls, the low-fidelity TLS polymerases also gain access to undamaged DNA where their inaccurate synthesis may actually be beneficial for genetic diversity and evolutionary fitness.