The first 4 years of the 21st century have been an exciting time for tuberculosis (TB) research. After more than a half-century, the first new vaccines for TB are beginning to enter human clinical trials. Based on advances in proteomics and genomics, new vaccine candidates are filling the preclinical pipeline and our understanding of the natural history of M. tuberculosis infection is expanding rapidly. This review summarizes the developing consensus on the BCG vaccine and its limitations and discusses clinical trials of some of the new vaccines intended to supplement or replace it.