Multidrug-resistant tuberculosis is one of the major obstacles that face the tuberculosis eradication efforts. Drug-resistant Mycobacterium tuberculosis clones were initially disregarded as a public health threat, because they were assumed to have paid a high fitness cost in exchange of resistance acquisition. However, some genotypes manage to overcome the impact of drug-resistance conferring mutations, retain transmissibility and cause large outbreaks. In Argentina, the HIV-AIDS epidemics fuelled the expansion of the so-called M strain in the early 1990s, which is responsible for the largest recorded multidrug-resistant tuberculosis cluster of Latin America. The aim of this work is to review the knowledge gathered after nearly three decades of multidisciplinary research on epidemiological, microbiological and immunological aspects of this highly successful strain. Collectively, our results indicate that the successful transmission of the M strain could be ascribed to its unaltered virulence, low Th1/Th17 response, a low fitness cost imposed by the resistance conferring mutations and a high resistance to host-related stress. In the early 2000s, the incident cases due to the M strain steadily declined and stabilized in the latest years. Improvements in the management, diagnosis and treatment of multidrug-resistant tuberculosis along with societal factors such as the low domestic and international mobility of the patients affected by this strain probably contributed to the outbreak containment. This stresses the importance of sustaining the public health interventions to avoid the resurgence of this conspicuous multidrug-resistant strain.