The thoracic cavities receive increasing attention in toxicology, because inhaled fibers and (nano)particles can reach these cavities and challenge the local lymphoid tissues. The thoracic and abdominopelvic cavities are controlled by the serosal immune system with its special, loosely organized lymphoid clusters, namely the fat-associated lymphoid clusters andmilky spots, which together can be denoted as serosa-associated lymphoid clusters. These clusters house numerous innate lymphoid cells, namely the nonconventional, innate B lymphoid cell and innate lymphocyte type 2 populations. The fat depots in the thorax play a significant role in the serosal immunity, and they can bemodulated by health issues such as metabolic syndrome. The serosal immune systemoperates in a unique way at the interface of the innate and acquired immunity and therefore exposure-relatedmodulation of the systemmay have a distinct impact on the body's immunity. To add to the investigation of the serosal immune systemin the thorax, this review describes the (micro)anatomy of the immune system in relation to exposure, with a focus on the rat andmouse as preferred species in toxicology and immunology. © The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.