Tuberculosis (TB), an infectious disease that most commonly affects the lungs, remains a global health threat. TB is caused by host-adapted mycobacteria, with Mycobacterium tuberculosis being the predominant human pathogen, while Mycobacterium bovis infects cattle and can cause zoonotic TB in humans. Regardless of the species involved, granulomas are the hallmark tissue lesions of TB. These multicellular structures exhibit varying degrees of cellular complexity, are dynamic and show considerable diversity within and between hosts. Mycobacteria infect myeloid cells, which are critical for antimycobacterial defense, but can also be detrimental to the host by contributing to immunopathology. The heterogeneity of myeloid cells, their cellular interactions and reactivity in different niches, including hypoxic regions of granulomas, determine the outcome of TB. We use tractable animal models to reveal early interaction partners of myeloid cells in the infected lung and model TB granulomas using multi-species approaches. Tissue and lesion microenvironments modulate immune responses to mycobacteria and are key to designing interventions against TB in humans and animals.