Receptors for nucleotides regulate all aspects of vascular function. Here, the role and function of P2Y receptors in vascular endothelium and smooth muscle cell proliferation are explored. In both cell types the presence of multiple P2Y receptors is commonplace; however, the identity and role of these receptors is dependent on the vessel of origin. This is clearly seen with endothelial cells. The commonest observation is coexisting P2Y 1 and P2Y 2 (or P2Y 4 ) receptors coupled through inositol 1,4,5-trisphosphate production to Ca 2+ mobilisation. However, in some endothelial cells other P2Y receptors are present. Brain microvascular endothelial cells, for example, exhibit a variety of responses with profiles which cannot be fully explained by cloned P2Y receptors, and which are coupled to diverse receptor-effector mechanisms. These include p42/p44 mitogen-activated protein kinase activation, enhanced cyclic AMP synthesis and raised cytosolic Ca 2+ in the absence of detectable rises in inositol 1,4,5-trisphosphate. These responses can be expected to influence endothelial prostacyclin and nitric oxide production, permeability, adhesion factor expression, and leukocyte-endothelial interaction. P2Y receptors also regulate proliferative responses. Previously, data has been presented indicating that nucleotides acting on P2Y receptors can enhance cell proliferation in response to other agents. Here, we discuss evidence that UTP is an antiproliferative regulator in human vascular smooth muscle cells and that P2Y 4 receptors may be involved in this response. Drug Dev.