The genetic analysis of mechanisms of pathogen resistance in the nematode Caenorhabditis elegans has revealed a role for evolutionarily conserved signaling pathways that are required for innate immunity in a wide range of organisms, from worms to mammals. C. elegans represents one of the more simple host organisms in which mechanisms of host defense can be dissected, and the use of C. elegans presents the researcher with a wide array of genetic and genomic tools to probe the host-pathogen interface. The study of host defense mechanisms in C. elegans continues to provide an ancient evolutionary perspective on innate immunity, which may generate insights into the conserved processes in phylogenetically diverse host organisms, including humans.