Publisher Summary This chapter discusses early immunotoxicity regulations and recent immunotoxicity guidelines as the regulatory aspects of immunotoxicity evaluation. Before requiring for nonclinical immunotoxicity testing, it must be clearly established which hazards related to immunotoxic effects have been identified, what are their incidences, and what are their severity degrees. Overall immunotoxic effects are relatively common and associated with significant morbidity and mortality. Hypersensitivity reactions are the most frequent immunotoxic effects and some are life-threatening. Autoimmune reactions, although probably rare, can result in massive epidemics with significant mortality as demonstrated by the Spanish toxic oil syndrome. Another issue is the acceptability of risk. Although there is no widely accepted definition of what an acceptable toxic risk is, immunotoxic effects can result in severe complications so that many immunotoxic effects can be considered as unacceptable risks. Recently released regulations in immunotoxicology will have and already have had a major impact on the development of immunotoxicology.