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The immunogenetic dictum "not all the infected develop the disease" can best be explained by a "Lotus and Cactus" model. Lotuses grow in ponds and cacti in deserts: analogously, we can say that tubercle patient’s lung (genetic makeup) functions as an ideal ’broth’ for Mycobacterium tuberculosis (M.tb) germs to grow, but not the lungs of an endemic control. HLA association studies from Europe to Asia since 1983 till date, have shown a persistent HLA DR2 (15) association. Further, HLA DR2 and non-DR2 endemic controls showed disparate patterns of immune responses and gene expressions. The host and pathogen MHC diversities, Th1-Th2 paradigm and cytokine circuits all may play a crucial role in TB susceptibility. It is possible to decipher the protective immunity by controlling the known confounders - epidemiological, demographic, socio-biological and also host and pathogen diversities. This has become significant with our understanding on the ’out of Africa’ migration and neolithic co-dispersal of M.tb with modern human. Divergence and expansion of various MHCs (eg HLA-DRB1*15, HLA-B*57) and non-MHC alleles in various continents might be responsible for the skewed transmission and distribution of the infectious diseases around the globe. The ’Lotus and Cactus’ model proposed here exemplifies this. A holistic genetic epidemiology approach employing modern tools is the need of the hour to better understand infectious disease susceptibility. (C) 2015 Elsevier B.V. All rights reserved.