The generation of animal models in which individual members of a gene family are genetically altered is a particularly attractive way to elucidate their function-Members of the Rel/NF-kappa B/I kappa B family constitute an important network of transcription factors and regulatory proteins that control the expression of numerous cellular and viral genes crucial for a variety of processes. A few examples are developmental pattern formation and immune response in Drosophila, viral replication, and immune, inflammatory, acute phase and stress responses in vertebrates. The findings from knockout and transgenic mice developed to study Rel/NF-kappa B/I kappa B function in vivo are reviewed here. In general, these studies point to the essential role of these factors in the development and function of the vertebrate immune system.