With the prevalence of therapeutic monoclonal antibodies (mAbs) in the biopharmaceutical industry, the use of mammalian cell culture systems, particularly Chinese hamster ovary (CHO) cells, has become the main method for the production of therapeutics. Despite their similarity to human cells, one major challenge of mammalian cell based biopharmaceutical production is controlling aberrant glycosylation, especially glycans with five to nine mannose residues-high mannose glycoforms. Glycosylation plays a critical role in determining the therapeutic profile of therapeutic glycoproteins; high mannose glycoforms in particular have been shown to have a significant impact on clinical efficacy and pharmacokinetics. Thus, producing glycoform profiles with consistent levels of high mannose is necessary to reduce batch-to-batch therapeutic variability and to meet regulatory standards. Studies have shown that high mannose glycoforms can be modulated through the genetic engineering of cell lines, addition of inhibitors to key enzymes in the glycosylation pathways, and varying cell culture conditions. Focusing on these three types of techniques, this review will examine and critically assess current methods for high mannose glycosylation control and future developments in this area. (C) 2014 Wiley Periodicals, Inc.