A growing body of evidence indicates that Mtb actively modulates host membrane dynamics by arresting phagosome maturation, preventing phagosomal acidification, and inhibiting autophagy. How Mtb achieves these outcomes remains unknown. Because i) many intracellular pathogens secrete virulence factors that modulate host membrane dynamics, ii) Mtb secretes ~10% of its proteome and iii) Mtb actively engages multiple membrane-dependent host processes, we hypothesized that some secreted mycobacterial proteins might interact with host membranes to influence the outcome of infection (Fig. 2, 3). We employed a novel high-throughput live-dead screen in Saccharomyces cerevisiae to screen two hundred putative Mtb effectors for membrane binding and identified ~50 membrane binding effectors. We are have extensively characterized one effector, Mpt64, a highly secreted and immunogenic protein of unknown function, and are now further characterizing multiple other effectors for their virulence activities.