Immunotoxicity is defined as deleterious effects of a xenobiotic on the functioning of the immune system. Immunotoxic xenobiotics can be natural toxins, chemicals, or pharmaceuticals. Immunotoxicants are considered to be a high risk to human health, because immunotoxicity may be associated with high morbidity and mortality, and humans are continuously exposed to a range of immunotoxic substances, a considerable proportion of which are man-made industrial chemicals or pharmaceuticals. In order to minimize the risk of public exposure to such immunotoxic chemicals and drugs, the regulatory authorities have developed guidelines for safety testing, before these compounds come to the market. Toxicogenomics is the application of genomics technology in toxicology research. The basic principle of the toxicogenomics approach is that the effect of a toxic compound is determined by comparing gene expression profiles of exposed samples to non-exposed samples, which can then be used to classify the compounds with respect to their toxicity. This chapter discusses the structure of the human transcriptome, and the tools that are available to quantify alterations of the human transcriptome, to identify mechanisms of immunotoxicity, and classify compounds by their toxicity. The chapter also details a novel tiered in vitro approach for immunotoxicity risk assessment.