Gene and cell therapy offer new modalities in medicine for a wide-range of diseases. Despite the potential of such therapies, technical challenges – such as the precision and low efficiency of current genomic engineering tools – restrict their development and application. We will present a safe strategy for robust and efficient engineering of cells using CRISPR-Cas systems. Our method enables the rapid generation of a homogenous cell population with bi-allelic integration of a DNA cassette at the selection locus, without clonal isolation.