Over thousands of years microbes and mammals have co-evolved, resulting in extraordinarily sophisticated molecular mechanisms permitting the organisms to survive together. Mycobacterium tuberculosis is one of the best examples of successful co-evolution, since the bacilli have infected one third of the human population, but in 90% of the cases without causing overt disease. Despite this, increasing incidence of Human Immunodeficiency Virus (HIV) infection and the emergence of drug-resistant strains means that tuberculosis is in fact an extremely serious emerging threat to global health. Decades of work have focused on the interaction of this pathogen with its established cellular host, the macrophage, but still novel therapeautics remain elusive. While the macrophage is clearly important, recent evidence suggests that understanding the role of dendritic cells, which are key regulators of immunity, may be a crucial step in identifying new means of controlling this disease. Novel technologies, in particular genome-wide transcriptome analyses, are advancing our ability to dissect the complex dynamic relationships between dendritic cells and mycobacteria, highlighting new areas for study that have not been previously explored.