Specificity is perhaps the most enigmatic property of hormonemediated signaling pathways, especially when one considers that more than 30 hormones employ the ubiquitous second messengers, Ca, phospholipid, or cAMP, to relay messages from the cell membrane to intracellular effectors. In most cases the net signaling effect is to activate protein kinases or phosphoprotein phosphatases, which, in turn, alter the phosphorylation state of cellular target proteins. Although both enzyme classes have been intensely researched since the late 1950s, it is still unclear how individual hormones activate the correct pool of kinase or phosphatase to trigger specific intracellular events. One explanation that has recently attracted attention is a “targeting hypothesis” proposing that phosphorylation events are controlled in part by where kinases and phosphatases are located in the cell (1). In accordance with this proposal, it has become apparent that intracellular targeting of both enzyme classes is determined by association with “targeting subunits” or “anchoring proteins.” While there have been several general reviews on this subject (1–3), this article will focus on subcellular targeting of the cAMP-dependent protein kinase (PKA).