The presence of uracil in DNA calls for rapid removal facilitated by the uracil-DNA glycosylase superfamily of enzymes, which initiates the base excision repair (BER) pathway. In humans, uracil excision is accomplished primarily by the human uracil-DNA glycosylase (hUNG) enzymes. In addition to BER, hUNG enzymes play a key role in somatic hypermutation to generate antibody diversity. hUNG has several isoforms, with hUNG1 and hUNG2 being the two major isoforms. Both isoforms contain disordered N-terminal domains, which are responsible for a wide range of functions, with minimal direct impact on catalytic efficiency. Subcellular localization of hUNG enzymes is directed by differing N-terminal sequences, with hUNG1 dedicated to mitochondria and hUNG2 dedicated to the nucleus. An alternative isoform of hUNG1 has also been identified to localize to the nucleus in mouse and human cell models. Furthermore, hUNG2 has been observed at replication forks performing both pre- and post-replicative uracil excision to maintain genomic integrity. Replication protein A (RPA) and proliferating cell nuclear antigen (PCNA) are responsible for recruitment to replication forks via protein-protein interactions with the N-terminus of hUNG2. These interactions, along with protein degradation, are regulated by various post-translational modifications within the N-terminal tail, which are primarily cell-cycle dependent. Finally, translocation on DNA is also mediated by interactions between the N-terminus and DNA, which is enhanced under molecular crowding conditions by preventing diffusion events and compacting tail residues. This review summarizes recent research supporting the emerging roles of the N-terminal domain of hUNG.