Inflammation has a key role in a vast range of central nervous system diseases. Under acute and chronic neurodegenerative conditions, resident microglia and astrocytes and blood-borne immune cells concur to neuroinflammation and remodeling/repair at the inflammed site. Distinct inflammatory cell states characterized by either a beneficial or a detrimental phenotype have been identified, depending upon the timing after the initial insult and activation by specific pro- or anti-inflammatory molecules. Of note, quiescent adult neuroprogenitor cells located in both brain's neurogenic areas and parenchyma have been recently shown to interact with immune cells and actively participate to restore function. Among other systems, extracellular nucleotides and their receptors have emerged as early alerting signals in inflammation and as key players in orchestrating the release of inflammatory molecules and the interaction between different cell types. Here, we revise the state of the art in this expanding field with the final aim of unveiling whether new purinergic-based therapies may be useful to halt excessive inflammation and foster endogenous repair in neuroinflammatory disorders.