TNF and its receptor, TNFR1, are members of the TNF superfamily and play important roles during infection by orchestrating an inflammatory response. The key role that TNFR1 signaling plays in host defense singles it out as a frequent target of pathogen manipulation. This review describes how the TNFR1 signaling pathway is attacked by pathogen virulence factors and how the different TNFR1 signaling pathways, in particular the death signaling response, have evolved to counteract these pathogen manipulations. We examine recent data showing that other 'Death Receptors' in the TNF superfamily, namely TRAIL-R and Fas, also participate in the immune response to pathogens. Finally we explore how knowledge of the inhibition of these pathways is being translated for clinical applications.