Adenylyl cyclases (ACs) are effector enzymes downstream of various G protein-coupled receptors (GPCRs) and ion channels that transduce signals via the catalysis of adenosine triphosphate (ATP) to cyclic adenosine 3',5'-monophosphate (cAMP). In line with the many roles of the numerous GPCRs and ion channels, modulation of ACs leads to a variety of physiological effects dependent on the AC isoform, interaction partners, and tissue localization. Humans encode nine membrane-bound ACs that are organized into four groups based on their regulatory mechanisms to various intracellular stimuli. Group 1 ACs include AC1, AC3, and AC8 and are characterized by their positive modulation by Ca 2+ /Calmodulin (CaM) although AC3 is conditionally stimulated by this complex and requires the presence of additional G protein subunits. Group 2 ACs include AC2, AC4, and AC7 and are conditionally activated by G protein βγ (Gβγ) subunits. Group 3 ACs include AC5 and AC6 and are negatively modulated by Ca 2+ . Finally, Group 4 contains only AC9, which is the lone isoform relatively insensitive to forskolin, an allosteric agonist of ACs.