Transgenic mutagenesis in whole animals has become without doubt the most rewarding approach to analyse gene structure, expression, and function. In the TNF field, much of what we now question about TNF/TNF receptor function is based, to a large extent, on what we have already learned by overexpressing these molecules in transgenic mice or by ablating their expression in knockout systems. In addition, a clearer view of the involvement of these molecules in disease pathogenesis has emerged, and useful models for human disease have been generated. In this overview, we summarise our experience with TNF transgenic and knockout systems, and highlight advances made in our understanding of the role played by TNF and its receptors in immune regulation and in the pathogenesis of infectious, inflammatory, and autoimmune disease.