Ca2+ and cAMP are the archetypical second messengers that regulate cell physiology and which have established the paradigms for second messenger signalling. It is clear that these two second messengers modulate each other’s activities at numerous levels to yield responsive and elegant control over cellular processes. A particularly important and approachable interaction is the modulation by Ca2+ arising from store-operated Ca2+-entry of adenylyl cyclase activities in non-excitable cells. The same detail is not available for the interaction that arises by Ca2+ arising from L-type channel and adenylyl cyclases (ACs), although such modulation certainly occurs in both neurons and cardiomyocytes.Powerful tools have been developed for the dissection of these interactions in live cells by using fluorescent sensors for both Ca2+ (based on GCamps) and cAMP (based on EPAC) which are tethered to adenylyl cyclases. Tethering ACs with these sensors has no effect on their responsiveness or targetting. Application of these sensors have uncovered dynamic behaviours of both Ca2+ and cAMP in the domains of the ACs that are distinct from transitions of these messengers in the cellular cytosol. Indeed Ca2+-sensitive ACs report quite distinct Ca2+ and cAMP signals to those reported by Ca2+-insensitive ACs in response to the same signal. These sensors have also been used to dissect the composition of the complex that mediates the selective sensitivity of the Ca2+-stimulated AC, AC8, to store-operated Ca2+-entry (SOCE). Application of these sensors in combination with siRNA knockdown of target proteins (along with other complex dissection techniques, such as FRET analysis between target proteins, mutagenesis, etc) has allowed the description of an intimate, direct-binding complex that forms between Orai1, the channel component of SOCE and the AC8.A newer version of the cAMP sensor, which is resistant to fluctuations in pH associated with L-type channel activity, has now been developed which will allow the cAMP and Ca2+ microdomains in excitable cells to be approached.