Microbial pathogens display remarkably sophisticated adaptations, often engaging their hosts in intricate biochemical cross talk. The large repertoire of virulence factors from pathogens modulate multiple pathways in eukaryotic cells from cytoskeletal structure, cell cycle progression, programmed cell death, endocytic trafficking, signal transduction, and more. Structural work with these virulence factors is illuminating many aspects of the host-pathogen interaction and providing new tools for understanding a variety of basic eukaryotic cellular processes. Finally, the growing library of such structures is uncovering general paradigms in the mechanisms by which pathogenic organisms manipulate the host.