Biopharmaceuticals are used extensively for the treatment of a number of chronic debilitating and fatal diseases such as cancer and inflammatory or autoimmune diseases. Although biopharmaceuticals are in general well tolerated, the development of anti-drug antibodies can impair their safety and efficacy. Assessment of immunogenicity is essential for a more effective and rational use of biopharmaceuticals, and is dependent upon the establishment of efficient standardized assays that allow direct comparison of immunogenicity data with clinical outcome. Although regulatory authorities recommend the use of cell-based assays that reflect the mechanism of action of the drug for the detection of neutralizing anti-drug antibodies, conventional cell-based assays are difficult to standardize and often give variable results. A number of strategies have been adopted to improve the performance of cell-based assays, including quantification of drug-induced proteins using either real-time RT-PCR or branched DNA to detect mRNA, or ELISAs to detect protein, bridging assays using immobilized cells and the use of reporter gene assays. The relative merits and limitations of each of these methods is reviewed herein.