NEIL3 is a DNA glycosylase that preferentially recognizes and removes oxidative base lesions from single-stranded DNA and DNA structures with single–double-strand junctions, such as replication fork branches. The enzyme excises hydantoin lesions (spiroiminodihydantoin and guanidinohydantoin) with particular efficiency, along with other oxidized bases including 5-hydroxyuracil, 5-hydroxycytidine, and thymine glycol. Beyond base excision repair initiation, NEIL3 plays a distinctive role in interstrand crosslink repair by cleaving one of the two glycosidic bonds comprising the crosslink, which avoids double-strand break formation while generating an abasic site that is processed by translesion synthesis polymerases. NEIL3 expression is induced during oxidative and inflammatory stress, regulated in part through oxidative modification of a G-quadruplex-forming sequence in its promoter 1. During DNA replication, NEIL3 acts cooperatively with NEIL1 to remove lesions from replication fork structures, with NEIL3 preferentially excising damage from single-stranded template regions 2. Clinically, NEIL3 overexpression associates with poor prognosis in pancreatic adenocarcinoma, lung adenocarcinoma, lower grade glioma, and kidney cancers, with overexpressed tumors showing elevated mutation burden and altered expression of homologous recombination and mismatch repair genes 3. In glioma, a circular RNA derived from NEIL3 (circNEIL3) promotes tumor progression and immunosuppressive macrophage polarization 4. NEIL3 thus represents both a DNA repair enzyme essential for genome stability and a potential biomarker and therapeutic target in selected cancers.