Purines and pyrimidines are indispensable molecules of life; they are fundamental for genetic code and bioenergetics. From the very early evolution of life purines have acquired the meaning of damage-associated extracellular signaller and purinergic receptors emerged in unicellular organisms. Ancestral purinoceptors are P2X-like ionotropic ligand-gated cationic channels showing 20-40% of homology with vertebrate P2X receptors; genes encoding ancestral P2X receptors have been detected in Protozoa, Algae, Fungi and Sponges; they are also present in some invertebrates, but are absent from the genome of insects, nematodes, and higher plants. Plants nevertheless evolved a sophisticated and widespread purinergic signalling system relying on the idiosyncratic purinoceptor P2K1/DORN1 linked to intracellular Ca2+ signalling. The advance of metabotropic purinoceptors starts later in evolution with adenosine receptors preceding the emergence of P2Y nucleotide and P0 adenine receptors. In vertebrates and mammals the purinergic signalling system reaches the summit and operates throughout all tissues and systems without anatomical or functional segregation. Copyright © 2020 Elsevier Inc. All rights reserved.