The immunomodulatory mechanisms of immunomediated therapeutic agents are not fully understood. Here, we report our current understanding of the immunomodulatory effects of clinically proven and clinically tried agents, and of potential candidate agents, such as decoy receptor 3 (DcR3). We have selectively reviewed their immunomodulation in EAE and MS. Demjen et al. showed that the neutralization of CD95L (FasL) promoted axonal regeneration and functional improvement in an injured animal model, suggesting that this therapeutic strategy may constitute a potent future treatment for human spinal injury [168] . DcR3 is a recognized member of the TNFR superfamily and is predominantly expressed in tumor cells, allowing them to evade immune attack [169] . DcR3 is a soluble receptor that binds to members of the TNF family and can competitively inhibit the binding of TNF to TNFRs [170] . FasL, LIGHT, and TNF-like molecule 1A (TL1A) are all confirmed ligands of DcR3 [171, 172] . When DcR3 binds to FasL, it inhibits FasL-induced apoptosis [169] . It has also recently been shown that DcR3 counteracts the effects of Th17 cells by interfering with FasL-Fas interactions [173] . We have demonstrated that DcR3 ameliorates EAE by directly counteracting inflammation and downregulating Th17 cells in situ [174] , implying that DcR3 downregulates the Th17 response and inhibits the inflammation of the CNS in situ during EAE by blocking ligand-receptor interactions, such as Fas-FasL, DR2-LIGHT, and/or DR3-TL1A. Therefore, we introduce DcR3, another immunomodulatory molecule, as a potential candidate for consideration in the clinical treatment of MS.