DNA polymerase lambda (POLL) is a DNA repair enzyme with dual polymerase activities that functions across multiple DNA damage response pathways. It possesses both template-dependent and template-independent (terminal transferase) polymerase activities, alongside 5'-deoxyribose-5-phosphate lyase activity, enabling it to participate in base excision repair of abasic sites and gap-filling reactions. Beyond base excision repair, POLL contributes to the resolution of DNA double-strand breaks through non-homologous end joining and homologous recombination pathways. Its multifaceted role in DNA repair positions it as relevant to cancer development, as reflected in associations with breast cancer, glioma, and hepatocellular carcinoma. POLL variants have also been implicated in rare developmental syndromes such as FRAXF syndrome and ciliopathies, underscoring its importance in maintaining genomic stability. The gene's involvement in somatic hypermutation of immunoglobulin genes further highlights its role in adaptive immune responses. Despite these disease associations, POLL's specific contribution to cancer predisposition and the therapeutic targeting of POLL-dependent pathways remain incompletely characterized in current literature.