The immune system is a host defense system comprised of both innate mechanisms able to rapidly recognize and respond to conserved pathogen associated molecular patterns (PAMPs) as well as adaptive mechanisms able to respond to a wide variety of non-conserved and conserved pathogen associated molecules. In vitro and in vivo studies have demonstrated that the kinetics and type of immune response triggered by pathogenic insults is a function of both the nature of the insult and the subsequent cross-regulatory interactions between the responding immune cells. In this context, the potential immunomodulatory influences of the nervous system have been often viewed as exerting minimal modulatory effects and thus of being largely irrelevant in the development of immune responses. Here, using a Saturday Night Live (SNL)-styled point:counterpoint format, we discuss whether and to what extent the nervous system can shape the responses of the immune system. Finally, we examine whether primary degenerative disorders of the CNS are likely to lead to alterations in immune function.