Abstract Immune cells infiltrate the CNS in many neurological diseases with a primary or secondary inflammatory component. In the CNS, immune cells employ shared mediators to promote crosstalk with neuronal cells. The net effect of this neuro-immune crosstalk critically depends on the context of the interaction. It has long been established that inflammatory reactions in the CNS can cause or augment tissue injury in many experimental paradigms. However emerging evidence suggests that in other paradigms inflammatory cells can contribute to neuroprotection and repair. This dual role of CNS inflammation is also reflected on the molecular level as it is becomingly increasingly clear that immune cells can release both neurodestructive and neuroprotective molecules in CNS lesions. It is thus the balance between destructive and protective factors that ultimately determines the net result of the neuro-immune interaction.