Purinergic receptors or purinoceptors are expressed in many mammalian cells and are activated by extracellular purines (adenine, purine nucleotides and nucleosides). Both adenosine (P1) and nucleotide/nucleoside (P2, grouped in P2X and P2Y subtypes) receptors exert important role in the inflammatory processes. The significative up-regulation of many purinoceptors located on the immune cells (neutrophils, eosinophils, monocytes, macrophages, mast cells and lymphocytes) in the course of inflammatory diseases supports the interpretation of their functions. New insights into the involvement of purinoceptors also in the neuro-inflammatory diseases (e.g., conditions of chronic inflammation associated with neurodegenerative diseases) are proposed. The identification of antagonists of purinergic receptors potentially useful to control inflammatory pathways represents the object of many studies reported in the recent literature. Aim of this review is to recapitulate the most recent data and experimental findings that highlight the critical, double edge, effect of these receptors in inflammation, making consistent the possibility to target them to control and regulate inflammation.