The increasing demand for recombinant therapeutic proteins coupled with advances in technologies allow research to develop approaches to improve the efficiency, yield, and quality of biopharmaceutical products from CHO cells. CHO DG44 cells used in this study were engineered to express erythropoeitin (EPO) as the model recombinant protein in a DHFR-based selection system. From a series of CHO-DG44 cell lines derived from a polyclonal population, one cell line expressed a notable change in growth phenotype during prolonged culture (10 weeks). This cell line (IJ4) exhibited prolonged growth, reached a greater density, and delayed cell death. The change in growth was reflected in an increased total yield of EPO, whilst the specific productivity of cell line IJ4 remained similar. The increased total yield of EPO presents a desirable goal for production and hence detailed 'omics studies were performed to identify factors associated with better cell growth and survivability.Two different 'omics analyses were performed (microarray transcriptomic and GC-MS metabolic profiling) to identify potential target genes and key metabolites associated with changes in growth profile. The -omics analyses identified a subset of genes (MMP20, PLA1A, POSTN, SLC46A3, and TOP2A), and a metabolic marker (farnesal) strongly associated with changes in cell growth and nutrient uptake. The use of complementary 'omics approaches to identify molecular markers has allowed an integrated model to be built, which explains how CHO cell phenotype can adapt to long-term culture, and this defines molecular approaches for cell line screening and engineering.