Multiple sclerosis (MS) is a progressive neurodegenerative disease affecting myelin and axons, which is perpetuated by autoreactive lymphocytes and other inflammatory cell types. Because of the multifactorial nature of this disease, therapies targeting a single process may not be sufficient to halt its progression. VIP and PACAP are two neuropeptides shown to regulate multiple aspects of innate and adaptive immunity, and can also act independently on neural cells to promote their survival and regeneration. Animal studies have proven the efficacy of these peptides for the treatment of several models of neural inflammatory disorders, including those which, like MS, have major Th1/Th17 components. In this review, the immunomodulatory actions of VIP and PACAP will be discussed, with particular emphasis on their potential significance in MS.