Signalling pathways involving the vital second messanger, cAMP, impact on most significant physiological processes. Unsurprisingly therefore, the activation and regulation of cAMP signalling is tightly controlled within the cell by processes including phosphorylation, the scaffolding of protein signalling complexes and sub cellular compartmentalisation. This inherent complexity, along with the highly conserved structure of the catalytic sites among the nine membrane-bound adenylyl cyclases, presents significant challenges for efficient inhibition of cAMP signalling. Here, we will describe the biochemistry and cell biology of the family of membrane bound adenylyl cyclases, their organisation within the cell, and the nature of the cAMP signals that they produce, as a prelude to considering how cAMP signalling might be perturbed. We describe the limitations associated with direct inhibition of adenylyl cyclase activity, and evaluate alternative strategies for more specific targeting of adenylyl cyclase signalling. The inherent complexity in the activation and organisation of adenylyl cyclase activity may actually provide unique opportunities for selectively targeting discrete adenylyl cyclase functions in disease. (C) 2017 Elsevier Inc. All rights reserved.