CRISPR-Cas9 genome editing has been widely adapted to cleave genomic DNA sequences of interest. Cellular repair of the CRISPR induced DNA double-strand breaks is dominated by error prone end joining pathways that outcompete inefficient homology-directed repair (HDR) that would allow precise introduction of a mutation present in a supplied synthetic DNA donor. To achieve predominant HDR, we studied the combinatory effect of inhibitory mutations in genes that are central to competing repair pathways.