Abstract: The present invention relates to a method of generating eukaryotic cells suitable for the expression of transgenes in said cells comprising (a) introducing a nucleic acid encoding a selectable marker responsive to a selecting agent into the nucleus of cells, wherein the level of expression of said selectable marker is proportional to the level of phenotypic responsiveness to said selecting agent; (b) selecting, among the cells obtained in step (a), for cells with a detectable expression of said selectable marker; (c) optionally propagating the cells selected for in step (b); (d) mutagenizing the cells selected for in step (b) or propagated in step (c) or allowing for the appearance of spontaneous mutations in the cells selected for in step (b) or propagated in step (c); and (e) selecting for cells displaying an increased expression of said selectable marker compared to the expression obtained in step (b).