It’s becoming increasingly apparent that precisely ‘where’ processes occur within the 3-D matrix of the cell and ‘who’ the partners are, is crucial to allow for effective intracellular signalling. Delineating these fundamental processes will give insight into not only normal signalling function but also pathological changes and thus is likely to provide ways to generate novel therapeutics and diagnostics. In this arena, studies of cAMP signalling have provided important paradigms. Isoforms of the cAMP specific phosphodiesterase-4 (PDE4) family have provided the paradigm for compartmentalised cAMP signalling, with their N-terminal portions shown to contain motifs acting as ‘zip codes’ for precise intracellular targeting of specific isoforms so as to assemble complexes that then orchestrate the formation and shaping of intracellular ‘clouds’ and gradients of cAMP. Distinct PDE4 isoforms control output through major cAMP effector proteins by binding directly to the cAMP-stimulated GTP exchange factor, EPAC and by binding indirectly with protein kinase A (PKA) through interaction with various members of the PKA anchor protein family (AKAPs). Distinct PDE4 isoforms also exert spatially constrained actions by interacting with signal scaffold proteins such as beta-arrestin, RACK1 and DISC1. PDE4s can be regulated through direct interaction with proteins such as AIP/Ara9/XAP2 and indirectly, through interaction with kinases such as ERK, which cause their phosphorylation. PDE4s are regulated by post-translational modification, including multi-site phosphorylation by ERK, PKA and as a consequence of PI3 kinase activation. Dominant negative constructs and peptide displacers allow insight into spatially constrained functions os specific PDE4 isoforms and point to the generation of novel, isoform-specific therapeutics. In this regard PDE4 selective inhibitors have been shown to have potential for treating COPD, RA, asthma, septic shock, spinal cord injury, depression and schizophrenia.