Biological response modifiers (BRMs) are natural proteins that alter immune responses and that have been developed as either immunosuppressive or immunostimulating drugs. These may include natural products such as β-glucans, or biotherapeutics such as monoclonal antibodies. Immunotoxicity testing of these immune modulators is not currently regulated by International Conference on Harmonization (ICH) guidelines and thus, many of the standard immunotoxicity tests are used for understanding the pharmacology of the molecule. Since many biotherapeutics are only cross-reactive in nonhuman primates (NHPs), the standard immunotoxicity tests may need to be adapted (since rodents are the standard species used for immunotoxicity testing of small-molecule therapeutics). Unanticipated effects on the immune system may or may not be related to the mechanism of action, but would then be considered as immunotoxicity. Immunogenicity must also be assessed, which is the immune response to the drug. All of these factors make immunotoxicity testing of BRMs a challenge to toxicologists working in this field.