Initially, the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) aroused major interest due to its preferential toxic effect against malignant cells. However, subsequent studies revealed that the TRAIL system, comprising the family of signal-mediating and decoy TRAIL receptors, (i) can also induce death of non-transformed cells, (ii) has potent immunoregulatory functions, and (iii) exhibits a unique expression pattern in the central nervous system (CNS). Indeed, TRAIL is not expressed within the human brain, while apoptosis-inducing TRAIL receptors are found differently distributed on neurons, oligodendrocytes, and astrocytes. These findings rule out a major contribution of TRAIL to the so-called "immune privilege" of the brain, in which local inflammation is limited, although such a role has previously been suggested for the CD95 (Fas) ligand belonging to the same TNF/nerve growth factor (NGF) family. If, under pathologic circumstances, the CNS is inflamed, immune cells such as macrophages and T cells upregulate TRAIL upon activation and use this death ligand as a weapon, not only against tumor cells but also against neurons and oligodendrocytes within the inflamed CNS. In parallel, a profound immunoregulatory impact of TRAIL on activation and proliferation of encephalitogenic T cells outside the brain has also been shown. Thus, these studies have uncovered a complex action of TRAIL on CNS pathology, indicating the possible value of targeted manipulation of the TRAIL system for the treatment of inflammatory neurodegenerative diseases such as multiple sclerosis.