In the CNS, chemokines and chemokine receptors are involved in pleiotropic physiological and pathological activities. Several evidences demonstrated that chemokine signaling in the CNS plays key homeostatic roles and, being expressed on neurons, glia and endothelial cells, chemokines mediate the bidirectional cross-talk among parenchymal cells. An efficient communication between neurons and glia is crucial to establish and maintain a healthy brain environment which ensures normal functionality. Glial cells behave as active sensors of environmental changes induced by neuronal activity or detrimental insults, supporting and exerting neuroprotective activities. In this review we summarize the evidence that chemokines (CXCL12, CX3CL1, CXCL16 and CCL2) modulate neuroprotective processes upon different noxious stimuli and participate to orchestrate neurons-microglia-astrocytes action to preserve and limit brain damage. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.