The conserved eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1) removes a diverse array of adducts from the end of DNA strand breaks. Tdp1 specifically catalyzes the hydrolysis of phosphodiester linked DNA-adducts. These DNA lesions range from damaged nucleotides to peptide-DNA adducts to protein-DNA covalent complexes and are products of endogenously or exogenously induced insults or simply failed reaction products. These adducts include DNA inserted ribonucleotides and non-conventional nucleotides, as well as covalent reaction intermediates of DNA topoisomerases with DNA and a Tdp1-DNA adduct in trans. This implies that Tdp1 plays a role in maintaining genome stability and cellular homeostasis. Dysregulation of Tdp1 protein levels or catalysis shifts the equilibrium to genome instability and is associated with driving human pathologies such as cancer and neurodegeneration. In this review, we highlight the function of the N-terminal domain of Tdp1. This domain is understudied, structurally unresolved, and the least conserved in amino acid sequence and length compared to the rest of the enzyme. However, over time it emerged that the N-terminal domain was post-translationally modified by, among others, phosphorylation, SUMOylation, and Ubiquitinoylation, which regulate Tdp1 protein interactions with other DNA repair associated proteins, cellular localization, and Tdp1 protein stability.