The genetic means of pathogenesis of Francisella tularensis are poorly understood. F. tularensis is able to survive and replicate within macrophages, and a virulence factor, MglA, has been identified that is essential for this ability. MglA regulates the transcription of genes necessary for intracellular growth, including those located within the Francisella Pathogenicity Island (FPI). The FPI genes are required for intramacrophage growth and virulence, and appear to encode a protein secretion system, but the exact function of individual FPI proteins remains to be determined. Additional regulatory factors required for virulence have recently been discovered, as well a number of virulence genes identified through transposon mutant screens. The role of surface components, including LPS, pili, and capsule, in F. tularensis virulence is also beginning to be illuminated. The identification of virulence genes has enabled the study of defined attenuated mutants as live vaccine strains against tularemia. As new components of the F. tularensis virulence gene repertoire are discovered, we will achieve a better understanding of how this bacterium interacts with the host and evadesimmune function, which will facilitate the development of therapeutic and preventive measures against tularemia.