Abstract: The levels of the second messenger cyclic nucleotides，cAMP and cGMP are carefully regulated in all cells by the activity of a series of adenylyl and guanylyl cyclases and cyclic nucleotide phosphodiesterases （PDEs）. Most of the functions of these second messengers are mediated by activation of cyclic nucleotide dependent kinases or other discrete cyclic nucleotide binding proteins. Furthermore，the regulation and function of all of these enzymes are greatly influenced by the cellular and subcellular compartments in which they are localized. In this talk I will discuss several examples of cAMP-regulated cellular function that depend on the simultaneous，coordinated phosphorylation of multiple control points as determined by phosphoproteomic analysis of cells treated with and without selective phosphodiesterase inhibitors. The data strongly suggest that multiple PDEs work in a synergistic manner to coordinate different functional pools of cAMP. These different pools in turn coordinate not one，but many different steps to yield the final control of cellular function. The data imply that we likely therefore will need to consider a number of new and revised ways to think about cAMP regulation of cellular functions and also about drug design. For example，several different PDEs may need to be inhibited in order to produce meaningful pharmacological effects. The data also imply that the much of this cAMP regulation occurs as stochastic processes in different compartments in the cell.