Recent advances in nuclease-based genome editing allow for the correction of many point-mutations causing diseases. However, correcting genetic alterations caused by larger chromosomal rearrangements remain challenging with this approach. Designer-recombinases promise to fill this gap as demonstrated by the development of a heterodimeric Cre-based site-specific recombinase system. This system can functionally correct a large gene inversion frequently found in patients with severe Hemophilia A.