Since the discovery of TNF-related apoptosis-inducing ligand (TRAIL) and its network of receptors, the majority of attention has focused on the clinical potential of manipulating this pathway in cancer therapy. However, the widespread expression of TRAIL under inflammatory conditions and the ability to induce both apoptotic and prosurvival signaling pathways has suggested that TRAIL plays broader roles in regulating immune processes. Two new studies now show that expression of TRAIL by neutrophils in the lung facilitates defenses against bacterial pathogens, whereas expression of TRAIL by cells within arterioles exacerbates vascular disease. These differentiating results highlight that the context of TRAIL signaling can determine whether the outcome is beneficial or pathogenic for the host.