Autoregulation of renal blood flow is an established physiological phenomenon, however the signaling mechanisms involved remain elusive. Autoregulatory adjustments in preglomerular resistance involve myogenic and tubuloglomerular feedback influences. While there is general agreement on the participation of these two regulatory pathways, the signaling molecules and effector mechanisms have not been identified. Currently, there a two major hypotheses being considered to explain the mechanism by which tubuloglomerular feedback signals are transmitted from the macula densa to the afferent arteriole. The adenosine hypothesis proposes that the released ATP is hydrolyzed to adenosine and this product stimulates preglomerular vasoconstriction by activation of A1 receptors on the afferent arteriole. Alternatively, the P2 receptor hypothesis postulates that ATP released from the macula densa directly stimulates afferent arteriolar vasoconstriction by activation of ATP-sensitive P2X1 receptors. This hypothesis has emerged from the realization that P2X1 receptors are heavily expressed along the preglomerular vasculature. Exposure of the renal microvasculature to ATP, or to P2X1 agonists evokes an exclusively preglomerular vasoconstriction that is most prominent in the afferent arteriole. ATP-dependent vasoconstriction and the components of autoregulatory behavior are blocked by L-type calcium channel antagonists. Inactivation of P2X1 receptors impairs autoregulatory responses while afferent arteriolar responses to A1 adenosine receptor activation are retained. Autoregulatory behavior is markedly attenuated in mice lacking P2X1 receptors but responses to adenosine A1 receptor activation remain intact. More recent experiments suggest that P2X1 receptors play an essential role in TGF-dependent vasoconstriction of the afferent arteriole. Interruption of TGF-dependent influences on afferent arteriolar diameter, by papillectomy or furosemide treatment, significantly attenuated pressure-mediated afferent arteriolar vasoconstriction in wild-type mice but had no effect on the response in P2X1 knockout mice. Autoregulation is impaired in hypertension. Assessment of afferent arteriolar responsiveness to P2 receptor stimulation revealed attenuated ATP-mediated afferent arteriolar vasoconstriction in kidneys subjected to 6 and 13 days of angiotensin II-dependent hypertension, compared to normotensive controls. Furthermore, in similarly prepared kidneys, responsiveness to P2X1 receptor stimulation was nearly abolished. Collectively, these observations support an essential role for P2X1 receptors in pressure-mediated autoregulatory behavior and strongly implicate P2X1 receptors in TGF-mediated afferent arteriolar vasoconstriction.