Genome engineering systems capable of producing large DNA edits are required for numerous applications. We explored the possibility of utilizing site-specific recombinases (SSRs) for this purpose, employing a panel of different enzymes from different recombinase families. SSRs have been demonstrated to achieve gene-sized DNA replacement via recombinase-mediated cassette exchange (RMCE), which precisely exchanges a region of genomic DNA flanked by heterospecific target sites with a similarly flanked DNA donor. However, RMCE with a single recombinase generally displayed insufficient efficacy, which can be elevated via dual-RMCE (dRMCE) with two distinctive recombinases. We will present optimal conditions of dRMCE, showcasing its therapeutic potential. By elucidating the optimal conditions of dRMCE, we drastically enhanced its efficacy to therapeutically meaningful levels. This study, along with directed-evolution and on-going research to re-direct the specificity of SSRs to defined genomic targets, can ultimately offer designer-recombinase induced gene replacement (DRiGR) as a powerful genome engineering system to correct for mutations spanned across a large genomic region, without the necessity of integrating wild type SSR target sites. The presented tools represent promising technology that we believe has potential for subsequent pre-clinical studies to prepare DRiGR for clinical applications.