Developing sensitive and specific bioanalytical assays for measuring the immunogenicity of biological therapeutics has become an integral component of the drug-development process. The strategy for measuring these immune responses involves performing sensitive screening assays that are capable of detecting low levels of both low- and high-affinity antibodies. However, having sensitive assays inherently results in a certain rate of false-positivity. Hence, developing steps to determine specificity in these assays is important to confirm the presence of antidrug antibodies. The specificity assays are defined by the ability of an assay to score a positive result if the serum sample contains an antibody that can bind and/or neutralize the therapeutic protein. Here, we discuss the methodologies for determining specificity in the bioanalytical assays used for measuring antidrug antibodies. These methods will provide investigators and regulators with guidelines to develop and review assays to measure antidrug antibodies, which can specifically interfere with the actions of the drug and/or influence the safety profile of the therapeutic proteins.