Evolution has led to efficient cooperation between processes at the cellular level. This embodies the combinatorial complexity of transferring information through nucleic acids and proteins, and information processing that involves the diffusion of primary ligands and ⁄or second messengers. Consequently, compartmentalization is critical in the coordination of bioprocesses. Compartments exclude certain proteins and separate unrelated reactions, and favor proper cooperative behavior by decreasing the search time for an enzyme to find a substrate, or for a ligand to find a receptor. Compartments are formed from membranes, which these permit complex control systems that may involve conformational or electronic state changes in receptors or channels, and thereby play a crucial role in cell architecture and cell biochemistry. In addition, the cell membrane harbors structurally distinct entities, such as lipid rafts, rafts-like structures, caveolae; these are devoted to trafficking and signalling via their finetuned competence in selectively containing, or excluding, molecules such as receptors, transducer ⁄ adaptor and effector proteins. This can lead to highly sophisticated cellular diversity in response to common epigenetic factors and ⁄or modifications in the extracellular milieu. In this context, alveolar epithelial cells involved in gas exchange and the secretion of surfactants in the lung, or alveolar macrophages responsible for the clearance of exogenous particulate materials, are very different from, but can share many common features with, electrically excitable neurons receiving, processing and transmitting information throughout the whole body, or microglial cells clearing the entire nervous system of damaged neurons and infectious agents. One of the interacting biomolecular networks present in the compartments of the plasma membrane, the ‘purinome’, regulates the biological effects of extracellular purine ⁄pyrimidine ligands, participating in the extracellular release of nucleotides through non-lytic and non-exocytotic mechanisms; in nucleotide catabolism by ectonucleotidases; in binding of nucleoside di ⁄ triphosphates to P2 receptors or of nucleosides and their monophosphates to P1 receptors; and in intracellular reuptake of nucleosides through equilibrative and concentrative transporters. After a general ‘operational definition’ and brief characterization of the purinome (Volonte and D’Ambrosi), this minireview series analyses the subclass of ionotropic P2X receptors with regard to the properties of the submembrane microenvironment (lipid rafts) in which they are embedded (Garcia-Marcos et al.), and with emphasis on pathological conditions such as human lung diseases (Barth and Kasper) and neurodegenerative disorders and immune-mediated neuroinflammatory dysfunctions (Apolloni et al.). Discussions of the interactions of P2X receptors with other ion channels, their distribution in lipid rafts ⁄ caveolae in the alveolar epithelium, or the coupling of P2X receptors to a variety of intracellular signalling pathways, including cascades of protein kinases, lipid mediators and proteases, are included.