Despite widespread use of the BCG vaccine over the last 100 years, tuberculosis (TB) remains one of the leading infectious disease causes of morbidity and mortality worldwide, highlighting the urgent need for an improved vaccine. We currently have a limited understanding of the protective immune response to Mycobacterium tuberculosis (Mtb), the causative agent of TB, and this significantly hampers the development of novel efficacious vaccines. In addition, while essential to vaccine development, animal models do not fully reflect the spectrum of human infection and disease, leading to further roadblocks in vaccine development. Moreover, in humans, further work is needed to understand protective immune responses, especially tissue-specific immune responses, which then could be validated in animal models. Definition of protective immune responses could serve as correlates of protection, which would facilitate clinical trials of novel vaccines. Despite these challenges, there has been progress in recent years, with many promising candidate vaccines in the pre-clinical and clinical vaccine pipeline.