Neurodegeneration and signs of immune activation, with T cell infiltration, major histocompatibility complex class II expression and glial activation, occur in many neurological diseases. Although particular qualities of the inflammatory response have been proposed to be of importance, still very little is known about the exact factors that determine susceptibility to neurodegeneration. Mechanistic studies have yielded conflicting results, where inflammation is suggested both to attenuate and aggravate loss of nerve cells depending on the circumstances. In this context experimental genetic dissection in relevant rodent models such as experimental autoimmune encephalomyelitis and mechanical nerve injury can be a valuable tool to identify important genes/molecules/pathways. We here review emerging evidence using this approach that indicates different pathways related both to adaptive and local innate immune responses, which determine strain-specific susceptibility to neuroimmune inflammation and neurodegeneration. Exact positioning of genes in these types of complex traits will be important for the understanding of pathogenetic mechanisms and to direct the focus of functional studies using classical experimental tools. Ultimately, a better knowledge about the interplay between the nervous system and the local and systemic immune system can define new ways of intervention in neurodegenerative processes.