Extracellular ATP signals through two families of cell-surface P2 receptors, the P2Y family of G-protein-coupled receptors and the P2X family of ligand-gated cation channels, whose activation by ATP, in many cases, results in elevation of Ca2+ in the cell. Several P2 receptor subtypes with varying affinities for ATP are expressed simultaneously in a number of tissues; however, the biological significance of such an extensive P2 receptor network remains unclear. Jeff Dixon and co-workers (p. 3615) now use osteoblasts as a model system to gain insight into this question. They find that Ca2+ signalling is activated by an extremely wide range of ATP concentrations that spans six orders of magnitude. The authors demonstrate that low concentrations of ATP (1 nM to 100 μM) act through P2Y receptors and result in a transient elevation of Ca2+, which in turn leads to only a brief nuclear localisation of nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) – a transcription factor that promotes osteoblast differentiation and is regulated by cytosolic Ca2+ – but without the expression of NFAT target genes. By contrast, high concentrations of ATP (300 μM to 10 mM) act through P2X7 and elicit sustained Ca2+-mediated NFATC1 signaling with a subsequent robust expression of NFAT target genes. These data suggest that an ensemble of P2Y and P2X receptors allow cells to sense ATP over a wide range of concentrations and to transduce this input into distinct cellular signals.