Aim. We aim to engineer Y-SSRs to make them suitable for therapeutic genome editing. By reprogramming their DNA-binding specificity to act on human genomic sequences, we aim to excise, integrate, invert or replace DNA sequences to develop curative therapies for genetic diseases. Conclusions. The development of ZFD-dependent recombinases provides a powerful tool for genome editing applications that combines the ease of ZFD targeting with the editing precision of SSRs. Our research markedly expedites the creation of highly effective and precisely targeted designer-recombinases. Specifically, the fusion of a non-specific recombinase guided by ZFD binding to its intended target site introduces a novel concept for the development of precision genome editing tools. This approach expands the repertoire of techniques available for precise genetic modifications, holding promising implications across diverse scientific and biomedical applications. We anticipate that the developed approach could be adapted to other DNA-binding domains and other DNA-modifying enzymes. If successful, this concept would open exciting perspectives for flexible, seamless, and precise genome surgery.