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Rickettsiae include diverse Gram-negative microbial species that exhibit obligatory intracellular lifecycles between mammalian hosts and arthropod vectors. Human infections with arthropod-borne Rickettsia continue to cause significant morbidity and mortality as recent environmental changes foster the proliferation of arthropod vectors and increased exposure to humans. However, the technical difficulties in working with Rickettsia have delayed our progress in understanding the molecular mechanisms involved in rickettsial pathogenesis and disease transmission. Recent advances in developing genetic tools for Rickettsia have enabled investigators to identify virulence genes, uncover molecular functions, and characterize host responses to rickettsial determinants. Therefore, continued efforts to determine virulence genes and their biological functions will help us understand the underlying mechanisms associated with arthropod-borne rickettsioses.