Leprosy, a highly disabling and stigmatizing infectious disease, is caused by Mycobacterium leprae and the newly discovered agent, Mycobacterium lepromatosis. Though treatable with antibiotics, leprosy has still not been eradicated, and around 200,000 new cases are reported every year worldwide, mainly in India, Brazil, and Indonesia. Tipping the balance towards leprosy elimination begins with improving our understanding of the pathogenesis and the transmission of the disease, which remains poorly understood. Current research on leprosy is markedly hindered by our incapacity to cultivate the leprosy bacilli on artificial media, as well as by the variation of the clinical forms of the disease. The rise of genomics in the 2000s has helped to get around these problems by opening new ways of studying organisms. Tools were developed to recover enough genetic material for downstream genomic applications; however, none of them is yet suitable for high throughput purposes. In this thesis, we describe an optimized DNA extraction method from skin tissue that allows direct whole-genome sequencing, and enabled us to obtain ~ 250 genome sequences of M. leprae from different geographical locations throughout the world. Firstly, this dataset deepened our insight into the phylogeny of M. leprae, and points to the ancestral strain originating in East Asia and/or Europe. In addition, analysis of more than twenty drug-resistant strains revealed mutations in candidate genes potentially associated with new biological mechanisms such as drug resistance. Moreover, we analysed isolates from restricted geographic areas and from recurrent cases, and show that the distinction between relapse and reinfection with a closely related strain can be made but this remains challenging. The whole genome sequencing of M. lepromatosis was achieved in 2015, and the discovery and use of new specific molecular detection methods allowed us to identify M. lepromatosis in the red squirrel population in the British Isles. In parallel, M. leprae was also discovered in red squirrels on Brownsea Island in the south of England. Though the risk of transmission from animals to humans is not yet clear, the discovery of a new animal reservoir for leprosy bacilli in a non-endemic country raises the question about the existence of other such reservoirs, especially in endemic countries, which could contribute to ongoing transmission. Reliable and sensitive methods for detection of leprosy bacilli are crucial for early diagnosis and monitoring the disease. We show that efficient cell lysis during extraction increases the yield of genetic material recovered from leprosy bacilli and significantly improves the sensitivity of diagnosis by PCR for all leprosy forms. Overall, our results highlight the impact and efficiency of genomics and whole genome sequencing for uncovering new biological mechanisms in unculturable bacteria such as the leprosy bacilli. Our results generated new hypotheses that await testing, and underline the massive potential of omics and bioinformatics for better understanding and fighting the disease.