3'-5'-Cyclic adenosine monophosphate (cAMP) is a pleiotropic intracellular second messenger generated in response to activation of G(s) protein-coupled receptors. In the heart, cAMP mediates the catecholaminergic control on heart rate and contractility but, at the same time, it is responsible for the functional response to a wide variety of other hormones and neurotransmitters, raising the question of how the myocyte can decode the cAMP signal and generate the appropriate functional output to each individual extracellular stimulus. A growing body of evidence points to the spatial organization of the components of the cAMP signalling pathway in distinct, spatially segregated signalling domains as the key feature underpinning specificity of response and data is emerging, indicating that alteration of spatial control of the cAMP signal cascade associates with heart pathology. Most of the details of the molecular organization and regulation of individual cAMP signalling compartments are still to be elucidated but future research should provide the knowledge necessary to develop and test new therapeutic strategies that, by acting on a limited subset of downstream targets, would improve efficacy and minimize off-target effects.