Adenylate cyclases (AC) type 5 and 6 comprise the calcium-inhibited family of adenylate cyclase isoforms. Here we review recent discoveries in the regulation of AC5 and AC6 with a focus on posttranslational modifications including glycosylation, nitrosylation, and phosphorylation by the cyclic AMP-dependent protein kinase (PKA), protein kinase C (PKC), and Raf1. We also describe novel signaling interactions such as Galpha(q)-mediated potentiation of AC6 activation. Novel regulators of AC5 and AC6, including small molecules and proteins that physically interact with AC5 and AC6 such as snapin, regulator of G protein signaling 2 (RGS2), protein associated with myc (PAM), and caveolin peptides are discussed. We also describe several recent studies that demonstrate the usefulness of transgenic or adenoviral overexpression of AC5 and AC6 in models for disease states such as cardiovascular hypertrophy. The discovery of novel regulatory mechanisms for AC5 and AC6 and their potential role in crucial physiological processes provide new avenues for research into therapeutic interventions targeting the cyclic AMP pathway.