The adenylyl cyclases (ACs) catalyze the production of the ubiquitous second messenger, cAMP, which in turns acts on a number of effectors and thus regulates a plethora of cellular functions. As the key enzymes in the highly evolutionarily conserved cAMP pathway, the ACs control the physiology of the cells, tissues, organs and organisms in health and disease. A comprehensive understanding of the specific role of the ACs in these processes of life requires a deep mechanistic understanding of structure and mechanisms of action of these enzymes. Here we highlight the exciting recent reports on the biochemistry and structure and higher order organization of the ACs and their signaling complexes. These studies have provided the glimpses into the principles of the AC-mediated homeostatic control of cellular physiology.