The failure of BCG vaccination to control the global tuberculosis epidemic and the spread of multidrug resistance underline the need for a better vaccine. Recent advances in molecular microbiology, gene therapy, and, last but not least, immunobiology, provide a rational basis for the development of more efficient vaccines against tuberculosis. The complete sequencing of the M. tuberculosis genome marked a turning point in tuberculosis vaccine research. The advent of genetic vaccination with either naked DNA, live recombinant, or artificial vaccine vectors holds out great promise of more efficient immunisation, in particular against intracellular pathogens such as M. tuberculosis. Our new understanding of how the immune response is orchestrated by dendritic cells makes it possible to design vaccines which specifically exploit the functions of these antigen presenting cells. Yet M. tuberculosis has kept many of its secrets, and although functional genomics, molecular medicine and immunotherapy are evolving rapidly, much empiric search and discovery are needed until the "captain of all these men of death" gives up his ghost to biotechnology.