Clinical effectiveness has driven the commercial success of monoclonal antibody (mAb) products. Mammalian cells are currently the preferred system for large-scale production as the mAbs produced are biochemically similar to human forms. The cell line generation process is tedious and time-consuming as clones with high productivity, stable long-term expression and good product quality are rare occurrences. Cell line generation efficiency and mAb quality can be improved through host cell engineering, vector optimization and high-throughput clone selection. Targeted integration into predetermined sites on the chromosome is a promising new area being explored. This review covers existing technology and recent progress made in improving various aspects of the stable cell line generation process for mAb production.