The replication of damaged DNA templates by translesion synthesis (TLS) is associated with mutagenesis and carcinogenesis. This perspective discusses the different levels at which TLS may be controlled and proposes a model for TLS of severely helix-distorting DNA lesions that includes a decisive role for the Rad9-Hus1-Rad1 DNA-damage-signaling clamp. The dual involvement of this clamp in both DNA-damage signaling and TLS may have profound implications in determining cellular responses to DNA damage.