POLH encodes DNA polymerase eta (Pol η), a Y-family DNA polymerase specialized in translesion synthesis (TLS)—the ability to insert nucleotides opposite DNA lesions that would otherwise stall replication. Pol η is particularly important for accurate bypass of UV-induced pyrimidine dimers, inserting the correct base opposite these lesions. Although it has low processivity, Pol η cooperates with the POLZ complex (comprising REV3L, REV7, POLD2, and POLD3) to complete lesion bypass. Pol η also plays roles in somatic hypermutation of immunoglobulin genes and replication fork stability. Notably, recent evidence suggests expanded functions beyond lesion bypass: Pol η is constitutively present at replication forks, efficiently synthesizes through difficult-to-replicate sequences, and is required for stability of common fragile sites. Biallelic POLH loss-of-function mutations cause xeroderma pigmentosum variant (XPV), characterized by severe UV sensitivity and dramatically increased skin cancer risk. While the population-level constraint (gnomAD LOEUF=0.85) indicates this gene is LoF-tolerant in heterozygotes, this is distinct from the clinical pathogenicity of biallelic variants. Additionally, elevated POLH expression is associated with cisplatin resistance in lung and bladder cancer, where alternative polyadenylation generates transcripts that escape microRNA-mediated repression 1. Germline POLH variants with reduced catalytic activity impair cellular tolerance to both UV radiation and cisplatin 2, suggesting that partial POLH dysfunction may contribute to individual susceptibility to these DNA damaging agents.