Structural genomics has become a powerful tool for studying microorganisms at the molecular level. Advances in technology have enabled the assembly of high-throughput pipelines that can be used to automate X-ray crystal structure determination for many proteins in the genome of a target organism. In this paper, we describe the methods used in the Tuberculosis Structural Genomics Consortium (TBSGC), ranging from protein production and crystallization to diffraction data collection and processing. The TBSGC is unique in that it uses biological importance as a primary criterion for target selection. The over-riding goal is to solve structures of proteins that may be potential drug targets, in order to support drug discovery efforts. We describe the crystal structures of several significant proteins in the M. tuberculosis genome that have been solved by the TBSGC over the past few years. We conclude by describing the high-throughput screening facilities and virtual screening facilities we have implemented for identifying small-molecule inhibitors of proteins whose structures have been solved.