Tuberculosis, caused by Mycobacterium tuberculosis, is one of the world's deadliest communicable diseases and present in all regions of the world. The Global Tuberculosis Report 2014 shows higher global totals for new cases and deaths in 2013 than previously, an estimated 9.0million people developed and 1.5million died from the disease. The disease affects both BCG-vaccinated and non-vaccinated people. A third of the world population is believed to be latently infected. Latent tuberculosis (LTBI) is an asymptomatic phase, but bacilli have the potential to reactivate the disease. The risk of developing active tuberculosis is around 10% in the case of LTBI, but this percentage can be higher among individuals with decreased host immunity, (e.g. newborns, seniors, HIV-positive or AIDS patients, people with diabetes, cancer patients, organ transplant recipients and people undergoing treatment for autoimmune diseases). Protein and/or peptide based immunodiagnosis and immunotherapy (vaccine) of tuberculosis require better understanding of the processes involved in the induction of the immune responses during bacterial infection as well as during the progression of the disease at cellular, and even at molecular level. There is a need to genome/proteome wide analysis and identification of proteins involved in specific immune recognition processes. The following chapter is aiming to outline recent progress in searching for relevant proteins including immunodominant T and B cell epitope regions of M. tuberculosis. We wish also to demonstrate that this complex task could only be achieved by applying novel, combined approaches (bioinformatics, theoretical and experimental) and strategies. Together with the brief references to early attempts, special focus was taken to survey findings related to the translation of these discoveries into the development of protein (e.g. fusion proteins) or synthetic peptide epitope constructs to be utilized in early, sensitive and specific diagnosis and/or efficient targeted therapy including vaccination in tuberculosis.