Ca2+-regulated adenylyl cyclases (ACs) are involved in many of the most sophisticated physiological events including, cardiac contraction, hormone secretion and neuronal function. Their ability to interact with Ca2+ allows discrete local feedback mechanisms that yield the pulsatility and rhythmicity that is a characteristic of elaborate homeostatic functions. The sensitivity of the ACs to Ca2+ is no passive by-product of responsiveness to generically elevated cellular Ca2+, but instead is an elaborately orchestrated result of adjacency to Ca2+-channels, which is brought about both by direct binding with channel elements and recruiting of other cellular factors.I will summarize evidence for the direct binding of the Ca2+-stimulated AC8 to the store-operated Ca2+-entry channel, Orai1, using both biochemical and cell biological methods, such as pull-down, peptide array, FRAP and FRET studies. The ability of these ACs to sculpt their microenvironment will also be demonstrated by their recruitment of the actin cytoskeleton and lipid rafts. Additionally, the value of using AC-targeted sensors for measuring both Ca2+ and cAMP will be shown in exploring the dynamics of these second messengers in AC microdomains. New sensors for measuring AC microdomains in excitable cells will also be described.The overall summary of these results is that ACs should be considered to be central scaffolding proteins which not only generate cAMP, but also actively recruit both their targets and their regulators to create a microenvironment in which the most delicate aspects of cAMP signaling occur. These AC microdomains may provide the most insightful level at which to address cAMP dynamics.