While ATP is recognized as an intracellular energy source for many biochemical reactions, it is now recognised it is also an important extracellular signalling molecule. ATP is involved in both physiological and pathological events in most cell types, and receptor subtypes have been cloned and characterised. An important goal of purinergic research today is to annotate the human genome with functional information regarding the role of genes for purinergic receptors, ectonucleotidases and transporters, in brain physiology and pathology. Insights into these roles have been gained also from studies of the various purinergic knockouts, and here we report on the generation of these purinergic receptor/ectonucleotidase-null mice. Recent X-ray structures of purinergic ligand-activated receptors provide promising templates to understand the molecular mechanism of receptor actions at the atomic level, and to deploy X-ray structures to be used for structure-based drug design. In the present work we also summarize recent findings about X-ray structures of ionotropic and metabotropic purinergic receptors and ectonucleotidases. A novel and prominent role as modulators of signal propagation in animal cells is played by microRNAs. By acting as genetic switches, they might become stringent regulators of the variety of cellular responses triggered by the dynamic interactions between purinergic receptors, nucleotides/nucleosides, transporters and ectonucleotidases. In this review we highlight data on the regulation of purinergic mechanisms by microRNAs. Finally, we would like to illustrate what information is still missing or needed for the acquisition of a more complete knowledge of purinergic signalling.