Regulation of receptors allows their responses to be modified rapidly and appropriately according to the needs of the environment. Multiple mechanisms are involved in the loss of sensitivity that follows exposure to agonists. Receptor sequestration, a rapid and transient event, and receptor downregulation, which requires more prolonged agonist exposure, contribute to this effect. However, in this article Bob Lefkowitz and colleagues focus primarily on the recent developments in understanding mechanisms of rapid desensitization involving receptor phosphorylation. Various molecular biological techniques have been used to demonstrate the important roles of two particular kinases--beta ARK and protein kinase A--in this regard.