Summary. Background: Adenosine diphosphate (ADP) is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors (GPCRs), the P2Y1 and P2Y12 purinergic receptors. Recently, we demonstrated that both receptors desensitize and internalize in human platelets by differential kinase-dependent mechanisms. Objectives: To demonstrate whether responses to P2Y1 and P2Y12 purinergic receptors resensitize in human platelets and determine the role of receptor traffic in this process. Methods: These studies were undertaken either in human platelets or in cells stably expressing epitope-tagged P2Y1 and P2Y12 purinergic receptor constructs. Results: In this study we show for the first time that responses to both of these receptors can rapidly resensitize following agonist-dependent desensitization in human platelets. Further, we show that in human platelets or in 1321N1 cells stably expressing receptor constructs, the disruption of receptor internalization, dephosphorylation or subsequent receptor recycling is sufficient to block resensitization of purinergic receptor responses. We also show that, in platelets, internalization of both these receptors is dependent upon dynamin, and that this process is required for resensitization of responses. Conclusions: This study is therefore the first to show that both P2Y1 and P2Y12 receptor activities are rapidly and reversibly modulated in human platelets, and it reveals that the underlying mechanism requires receptor trafficking as an essential part of this process.