Leprosy is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in humans. Leprosy is also known as Hansen's disease after GA Hansen who discovered it in 1873. The infection is curable but not preventable, and remains a major global health problem, especially in the developing world. Complex segregation analysis study suggests an oligogenic model of leprosy susceptibility stating that the patients carry susceptible allele's loci. The infection in humans is influenced by genetic variation (SNPs) in the associated genes, that is, genes that contribute to the innate immune recognition of mycobacteria. Recognition of mycobacteria by the adaptive immune system, involves products of human leucocyte antigen/major histocompatibility complex genes and effector responses of the immune system. Host genetics plays an important role in determining an individual's risk of developing clinical leprosy. Host susceptibility genetic susceptibility to leprosy is complicated by the genetics of Mycobacterium leprae , interaction between gene and environmental factors, gene–gene interactions and lastly ethnicity. The host immune response influences the course of infection (host–pathogen relationship) and provides an exciting challenge to understand the genetics of disease susceptibility and immunopathogenesis of leprosy. Key Concepts: Leprosy was identified as the first devastating disease of humans causing disability by the bacterial pathogen Mycobacterium leprae . Genomic data might be useful in the development of drugs and vaccines against leprosy. Despite widespread implementation of effective multidrug therapy, leprosy has not been eliminated. Complex segregation analyses have suggested a predominant genetic rather than environmental model for associations in leprosy. Recognition of mycobacteria by the adaptive immune system involving products of human leucocyte antigen/major histocompatibility complex genes and effector responses of the immune system (genes affecting cytokines, chemokines and immunomodulators). Direct involvement of SNPs in different genes in host genetic susceptibility to leprosy. Single nucleotide polymorphisms (SNPs) represent an important class of genetic variation, and SNPs within and outside coding sequences are under intense examination for possible associations or mechanistic links to disease. Haplotypes are combinations of two or more polymorphisms (SNPs in this case) within a single chromosome in an individual, which can be used as genetic markers. The availability of the M . leprae genome sequence and improved methodologies for molecular level diagnosis of the genetic basis of drug resistance in mycobacteria led to the development of molecular methods for drug‐susceptibility testing (DST).