β-Lactams are one of the most useful classes of antibiotics against many common bacterial pathogens. One exception is Mycobacterium tuberculosis. However, with increasing incidence of multidrug-resistant tuberculosis and a need for new agents to treat it, the use of β-lactams, specifically the combination of carbapenem and clavulanate, is now being revisited. With this attention, comes the need to better understand both the mechanisms of action of β-lactams against M. tuberculosis as well as possible mechanisms of resistance, within the context of what is known about the β-lactam action in other bacteria. M. tuberculosis has two major mechanisms of intrinsic resistance: a highly active β-lactamase and a poorly permeable outer membrane. Within the cell wall, β-lactams bind several enzymes with differing peptidoglycan-synthetic and -lytic functions. The inhibition of these enzymes may lead to cell death through several mechanisms, involving disruption of the balance of synthetic and lethal activities. Currently, all known means of resistance to the β-lactams rely on diminishing the proportion of peptidoglycan-synthetic proteins bound and inhibited by β-lactams, through either exclusion or destruction of the antibiotic, or through replacement or supplementation of target enzymes. In this review, we discuss possible mechanisms for β-lactam activity in M. tuberculosis and the means by which it may acquire resistance, within the context of what is known in other bacterial species.