Over many years, recombinant protein biologics developers have addressed product immunogenicity with a focus on the active pharmaceutical ingredient. Recently, immune responses to the native host cell proteins (HCP) have gained attention, as they too may have an effect on the immune response to the formulated drug, namely diminished drug safety and efficacy. The recent suspension of two clinical trials due to the presence of antibodies to Chinese Hamster Ovary (CHO) HCPs in subjects treated with a recombinant biologic clearly reveals the serious concern regulatory agencies attribute to contaminating HCPs. It appears that even minor amounts of CHO-derived HCP in the final formulation of therapeutics can potentially stimulate an immune response to these contaminants; of even greater concern are immune responses that may be cross-reactive with human proteins. Publication of the CHO-K1 genome and transcriptome provides an opportunity to gain insight into one of the most commonly used expression systems in recombinant protein production. We recently applied immunoinformatics tools to evaluate the immunogenic potential of CHO HCP. Rather than evaluate HCP for their intrinsic potential immunogenicity, we suggest that we should estimate their immunogenicity on a fine-tuned scale that accounts for regions that are homologous to human sequences. As more information on the exact identity of the HCP that drive immunogenicity emerges, the accuracy of this approach is likely to improve. :