Tuberculosis (TB) is a serious health issue in the developing world. Lack of knowledge on the etiological mechanisms of TB hinders the development of effective strategies for the treatment or prevention of TB disease. Human genetic study is an indispensable approach to understand the molecular basis of common diseases. Numerous efforts were made to screen the human genome for TB susceptibility by linkage mapping. A large number of candidate-based association studies of TB were conducted to examine the association of predicted functional DNA variations in candidate genes. Recently, the first genome-wide association study (GWAS) on TB was reported. The GWAS is a proof-of-principle evidence that justifies the genetic approach to understand TB. Further hypothesis-free efforts on TB research may renovate the traditional idea of TB genetic susceptibility as none of the candidate genes with important roles in containing Mycobacterium tuberculosis (MTB) infection was identified of association with active TB, whereas the TB-associated loci in the GWAS harbors no gene with function in MTB infection.