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The ability to secrete proteins is important to the pathogenesis of many bacteria. For gram-negative bacteria, the secretion system must deliver cargo through both an inner and outer membrane to reach a potential target. To date, there are six known gram-negative bacterial secretion systems, designated types I-VI secretion. For many highly pathogenic bacteria including Yersinia pestis and Salmonella typhimurium, secretion of protein effectors directly into target host cells is essential for virulence. Proteins secreted via the type III, IV, and VI pathways result in direct transfer of proteins across the host membrane and into the cytosol, and these systems will be the focus of the technology highlighted in this article. Although the function of effector proteins secreted by these systems varies among different pathogens, common virulence mechanisms are evident. One common function of many secreted virulence factors is the targeting of host cytoskeletal function in order to promote uptake or inhibit phagocytosis. Another is modulating host cell cytotoxicity by inhibiting or promoting cell death in order to suppress innate immune function or to establish a replicative niche. Finally, an important mechanism common to many secreted effectors is the manipulation of host immune signaling. Until recently, fully evaluating the functional targets of bacterial secretion in vivo during infection was extremely difficult.