Tuberculosis is the most lethal infectious disease globally, but the vast majority of people who are exposed to the primary causative pathogen, Mycobacterium tuberculosis (MTB), do not develop active disease. Most people do, however, show signs of infection that remain throughout their lifetimes. In this review, we develop a framework that describes several possible transitions from pathogen exposure to TB disease and reflect on the genetics studies to address many of these. The evidence strongly supports a human genetic component for both infection and active disease, but many of the existing studies, including some of our own, do not clearly delineate what transition(s) is being explicitly examined. This can make interpretation difficult in terms of why only some people develop active disease. Nonetheless, both linkage peaks and associations with either active disease or latent infection have been identified. For transition to active disease, pathways defined as active TB altered T and B cell signaling in rheumatoid arthritis and T helper cell differentiation are significantly associated. Pathways that affect transition from exposure to infection are less clear-cut, as studies of this phenotype are less common, and a primary response, if it exists, is not yet well defined. Lastly, we discuss the role that interaction between the MTB lineage and human genetics can play in TB disease, especially severity. Severity of TB is at present the only way to study putative co-evolution between MTB and humans as it is impossible in the absence of disease to know the MTB lineage(s) to which an individual has been exposed. In addition, even though severity has been defined in multiple heterogeneous ways, it appears that MTB-human co-evolution may shape pathogenicity. Further analysis of co-evolution, requiring careful analysis of paired samples, may be the best way to completely assess the genetic basis of TB.