Purpose of Review <p>We present a comprehensive view of the human and animal domain perspectives, implications and significant considerations on <i>M. tuberculosis</i> complex variants adapted to animals, with the aim to highlight the areas of overlap in these fields and the need for a unified approach to tackling this problem.</p> Recent Findings <p>Expansion of molecular and genomic diagnostic methods has led to improved discrimination between <i>M. tuberculosis</i> complex variants, which illuminated the greater role in clinical and veterinary medicine of some previously under-recognized organisms (e.g. <i>M. orygis</i>). Similarly, genomic epidemiology has been used to untangle the intricate transmission networks of these organisms, spanning the animal-human interface.</p> Summary <p><i>M. tuberculosis</i> complex is a diverse group of organisms with members capable of infecting both human and animal hosts, with animal-adapted variants also equipped to cross species barriers. This complex group of organisms can cause a spectrum of disease manifestations, however, the extent of the burden of animal-adapted <i>M. tuberculosis</i> strains in human and animals hosts is not always well recognized, owing to such factors as difficulties with sample collections, siloed approaches and inter-jurisdictional complexities, as well as paucity and variability of available targeted diagnostic methods. We describe here the current perspectives on disease burden and clinical manifestations of different animal variants of <i>M. tuberculosis</i> complex in both animal and human hosts, as well as the diagnostic landscape available to detect and differentiate members of the complex. We highlight that coordinated One Health approaches with effective collaboration of all relevant stakeholders is needed to comprehensively and successfully address this problem for the betterment of both the human and the animal health.</p>