Cyclic AMP regulates a multitude of cellular responses and orchestrates a network of intracellular events. In the heart, cAMP is the main second messenger of the β-adrenergic receptor (β-AR) pathway producing positive chronotropic, inotropic, and lusitropic effects during sympathetic stimulation. Whereas short-term stimulation of β-AR/cAMP is beneficial for the heart, chronic activation of this pathway triggers pathological cardiac remodeling, which may ultimately lead to heart failure (HF). Cyclic AMP is controlled by two families of enzymes with opposite actions: adenylyl cyclases, which control cAMP production and phosphodiesterases, which control its degradation. The large number of families and isoforms of these enzymes, their different localization within the cell, and their organization in macromolecular complexes leads to a high level of compartmentation, both in space and time, of cAMP signaling in cardiac myocytes. Here, we review the expression level, molecular characteristics, functional properties, and roles of the different adenylyl cyclase and phosphodiesterase families expressed in heart muscle and the changes that occur in cardiac hypertrophy and failure.