Microsporidia comprise a phylum of obligate intracellular pathogens related to fungi that infect virtually all animals. Recently, the nematode Caenorhabditis elegans has been developed as a convenient model for studying microsporidia infection in a whole-animal host through the identification and characterization of a natural microsporidian pathogen of this commonly studied laboratory organism. The C. elegans natural microsporidian pathogen is named Nematocida parisii, and it causes a lethal intestinal infection in C. elegans. Comparison of the genomes of N. parisii and its closely related species Nematocida sp. 1, together with the genomes of other microsporidian species, has provided insight into the evolutionary events that led to the emergence of the large, specialized microsporidia phylum. Cell biology studies of N. parisii infection in C. elegans have shown how N. parisii restructures host intestinal cells and, in particular, how it hijacks host exocytosis for nonlytic exit to facilitate transmission. Recent results also show how the host responds to infection with ubiquitin-mediated responses, and how a natural variant of C. elegans is able to clear N. parisii infection, but only during early life. Altogether, these studies provide insight into the mechanisms of microsporidia pathogenesis using a whole-animal host.