The human metabolic response to infection with M. tuberculosis has been investigated on the level of small metabolites found in the serum. The aim of the study was not only to propose new biomarkers that distinguish between latent infection and clinical TB, but also to study the underlying biological mechanism of disease progression. The characteristic metabolomes of three study groups were compared: healthy controls (TST-), latent infection (TST+) and clinical TB (TBactive). The relative levels of almost 500 distinct small molecular compounds were acquired, including amino acids, short peptides, fatty acids and nucleotides. These were analyzed in the context of TB infection and clinical TB progression. Classification analysis of the data set shows that the clinical TB patients can be dependably distinguished from the other groups and levels some compounds are characteristic for either healthy controls or subjects with latent infection. Several functional groups of compounds which differentiate the study groups could be reliably determined by clustering analysis. The functional links found in this study indicate a role of a number of biological processes in TB progression, and novel results are confirmed by targeted experiments.