Astrocytes and neuronal cells have been shown to release nucleotides by non-lytic, transport-mediated mechanisms. Released nucleotides elicit a broad range of physiological responses including neurotransmission, regulation of cardiovascular function, platelet aggregation, secretion of hormones, modulation of the immune response, protection in hypoxia and ischaemia, and control of cell proliferation and differentiation. Distinct effects of nucleotides like ATP and adenosine reflect differences in nucleotide receptor expression and the modulating role of nucleotide hydrolysis by ectonucleotidases. Current research is mainly focused on short-term effects of nucleotide receptor activation e.g. Ca2+ influx, activation of phospholipase C, regulation of adenylate cyclase, but less on the long-term trophic effects of nucleotides. Our laboratory has studied the trophic actions of nucleotides on the proliferation and differentiation of rat C6 glioma cells, often used as biochemical model system for astrocytes. These cells have oligodendrocytic and astrocytic progenitor properties and express the P2Y1, P2Y2, P2Y4, P2Y6, P2Y12 receptors and the A2B adenosine receptor. In these cells, differentiation towards an astrocyte type II is induced by elevation of the intracellular cAMP concentration. In this review, P2Y receptor-mediated short- and long-term effects on glial and neuronal cells are discussed in view of the results obtained with C6 cells. Long-term trophic effects of adenosine and uridine nucleotides are related to short-term events initiated in the cells upon P2Y receptor stimulation.