Years of intense research aimed at developing a new and improved vaccine against tuberculosis (TB) are now moving from the laboratories and into the field. Many groups have provided strong evidence for the potential of novel vaccines using a variety of different strategies and the most promising are just beginning to enter human safety trials. As research has developed over the years, the complexity of the TB situation at the global level and its influence on vaccine development strategies has become more and more clear. From being mainly focused on the development of a vaccine that could be given at birth and provide lifelong protection, it is now clear that the current goal may need to be a vaccine to be given to a population where the majority is already sensitized either by previous infection, exposure to other mycobacteria or by Bacille Calmette-Guerin vaccination. With the increasing awareness of the different immune mechanisms operating under those circumstances, such a vaccine still represents a significant challenge for immunologists and microbiologists working in this field.