β-adrenergic receptors enhance cardiac contractility by increasing cAMP levels and activating the cAMP-dependent protein kinase (PKA). PKA phosphorylates several key excitation-contraction coupling proteins, including L-type Ca2+ channels at the plasma membrane. However, PKA regulates numerous other effectors in cardiac myocytes, and notably nuclear effectors ultimately leading to hypertrophic remodelling and heart failure. In the last few years, our group has contributed to the recognition that physiological cAMP signaling is confined in specific subcellular domains and identified cyclic nucleotide phosphodiesterases (PDEs) as crucial regulators of compartmentalized cAMP signals and local PKA activity. This presentation will briefly summarize published data regarding the regulation of L-type Ca2+ current by type 4 phosphodiesterases (PDE4) and the implication for cardiac arrhythmias. It will then focus on the regulation of cytoplasmic versus nuclear PKA activity in cardiac myocytes, visualized by FRET-based A-kinase activity reporters targeted to these compartments. The role of PDEs as well as Ser/Thr phosphatases in the differential integration of the PKA response to β-adrenergic stimulation will be discussed.