Tuberculosis (TB), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. Pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. Cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. The host immunological reaction to Mycobacterium tuberculosis is implicated in driving the development of TB cavities. TB is characterized by a matrix-degrading phenotype in which the activity of proteolytic matrix metalloproteinases (MMPs) is relatively unopposed by the specific tissue inhibitors of metalloproteinases. Proteases, in particular MMPs, secreted from monocyte-derived cells, neutrophils, and stromal cells, are involved in both cell recruitment and tissue damage and may cause cavitation. MMP activity is augmented by proinflammatory chemokines and cytokines, is tightly regulated by complex signaling paths, and causes matrix destruction. MMP concentrations are elevated in human TB and are closely associated with clinical and radiological markers of lung tissue destruction. Immunomodulatory therapies targeting MMPs in preclinical and clinical trials are potential adjuncts to TB treatment. Strategies targeting patients with cavitary TB have the potential to improve cure rates and reduce disease transmission.