Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosisof infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spreadof mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediatedmacrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led tophosphorylation of FLIPS, which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggeredproteasomal degradation of FLIPS, which promoted activation of caspase-8 and apoptosis. Our findings identify a previouslyunappreciated signaling pathway needed for Mycobacterium tuberculosis–triggered macrophage cell death.