**1. Introduction**

The microbe *Mycobacterium tuberculosis* (MTB) is an ancient cohabiter with humans, infecting al‐ most 3 billion people worldwide, 10% of them developing clinical disease. The 20th century dream of eradicating the global scourge of tuberculosis (TB) evaporated with the failure of the old BCG vaccine to protect the populations at greatest risk, low compliance at following the complicated and lengthy treatment in countries with limited resources, which was followed by the spread of multiple-drug resistant (MDR) strains. Actually the situation has worsened with a peak of 9.4 millions of new clinical cases in 2009 and 1.7 million deaths/year [1,2,3].

However, it is intriguing to observe that the incidence and morbidity of the disease varies great‐ ly in different regions of the globe, being highest in Africa and Asia, as well as the response to BCG vaccination [1,4]. That, in spite of the fact that there are no structurally variable strains of MTB, therefore all have a similar virulence capacity. One important factor is the introduction of the human immunodeficiency virus (HIV) into areas and populations already having a high TB incidence [5], the resulting double infections having a disastrous effect. This is especially promi‐ nent in sub-Saharan Africa. But that factor alone can not explain the global epidemiological var‐ iability in the disease. Also, why only one in ten carriers of the microbe become clinically sick?

In order to address these questions, in the present chapter we will try to delve into the intri‐ cacies of the human immune response to MTB infection and to explore possible differences in the genetic regulation of the host immune responses in various human populations.
