Toxicologic pathology plays a crucial role in the identification and interpretation of substance-induced health effects. Histology of lymphoid organs is quite sensitive, although it does not flag every model immunotoxic substance. Subtle interferences of toxic compounds, like transmembrane signaling and cell activation, are often not detectable by conventional histology. The immune system by its very dynamic nature manifests a bandwidth in its morphological picture, hence the 'normal' state can be quite variable. Interspecies- and interstrain-dependent differences in the histophysiology of lymphoid organs should be taken into account, as well as the functional and morphological changes in lymphoid organs during life. Increased susceptibility to immunotoxicants may occur during periods of marked histophysiological changes in lymphoid organs. The high sensitivity at perinatal age for a number of immunotoxicants has received specific attention in immunotoxicity testing. In the interpretation of effects, it should be noted that particular components of lymphoid organs may be decreased in number (suppressed-involuted) or increased (stimulated-expanded), but that does not necessarily reflect the overall effects on the immune system.The chapter addresses the histology of lymphoid organs, including tertiary lymphoid structures. Toxicant-induced pathologies are presented and associated mechanisms of toxicity are discussed.