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The mechanisms involved in osteoblast and adipocyte differentiation from the common progenitor, mesenchymal stem cell (MSC) are not fully understood. The nucleoside, adenosine, exists in all cells and is known to be involved in cell growth, proliferation and apoptosis by interacting with four distinct receptors (Ai, A2A, A2b and A3). The aims of this study was to investigate the expression and function of adenosine receptors in 1) MSCs and as they differentiated into osteoblasts and adipocytes and in 2) mouse 7F2 and human osteoblasts and during their transdifferentiation to adipocytes. Rat MSCs and 7F2 osteoblasts expressed all four adenosine receptors. Osteoblast differentiation was associated with increases in A2A and A2B receptor expression and their activation stimulated the expression of alkaline phosphatase, core binding factor a1 and mineralisation. Adenosine also stimulated adipogenesis (lipid accumulation, peroxisome proliferator-activated receptor, CCAAT/enhancer binding protein a and lipoprotein lipase expression) of MSCs which was accompanied by increased A1 and A2A receptor expression. Transdifferentiation of 7F2 cells to adipocytes was associated with increased Ai, but decreased A2A and A2b receptor expression. Loss of A2 receptors in adipocytes was supported by reduced cAMP and extracellular signal regulated kinase responses to adenosine. Adenosine also stimulated transdifferentiation of human osteoblasts to adipocytes by inducing lipoprotein lipase and inhibiting alkaline phosphatase and osteocalcin expression. Overexpression of Ai receptors in 7F2 cells stimulated adipogenesis (lipid accumulation and lipoprotein lipase expression) whereas overexpression of A2b receptors stimulated alkaline phophatase expression and inhibited adipogenesis. These results show that adenosine receptor expression and function is involved in lineage specific differentiation or transdifferentiation A2B receptors are associated with MSCs and osteoblasts and Ai receptors with adipocytes. Targeting adenosine signal pathways may thus be useful as an adjunct therapy for the prevention or treatment of conditions in which there is insufficient bone or excessive adipocyte formation.