Defects in DNA polymerase (Pol) η result in a cancer-prone and UV-sensitive inherited syndrome, a variant form of xeroderma pigmentosum, suggesting that Polη plays a vital role in preventing UV-induced skin cancers. In fact, Polη can catalyze translesion synthesis (TLS) past prominent UV-induced lesions efficiently and accurately. However, Polη is intrinsically an error-prone DNA polymerase, like other TLS polymerases. Biochemical, structural and physiological studies revealed that Polη and other TLS polymerases participate in multiple mutagenic mechanisms, including somatic hypermutation of immunoglobulin genes. Protein-protein interactions between Polη and PCNA, TLS polymerases, RAD18 and DNA repair proteins, as well as their posttranslational modifications, have been shown to be important for regulating Polη.