Cyclic AMP and cyclic GMP regulate a vast array of cellular activity by modulating the function of molecular switches in the cell. The Cyclic Nucleotide Phosphodiesterases (PDEs) function as key players in controlling the duration and magnitude of these cellular responses by reducing the intracellular levels of cAMP and cGMP. The level of complexity of this role is reflected by the increasingly recognized fact that different PDEs are able to exert control of compartmentalised pools of cAMP and cGMP. The 2008 meeting is the sixth Cyclic Nucleotide Phosphodiesterases Gordon Research Conference and addresses ground breaking developments in the field. Fundamental research into the structure/function (derived from X-ray crystallography) of PDEs and regulation and compartmentalisation in mammalian cells and lower organisms will be discussed. A major theme of the meeting is how these fundamental studies inform on the role of PDEs in systems biology, with particular focus on the central nervous and cardiovascular systems. This is complemented by thorough examination of therapeutic utilities of PDE inhibitors, which is now timely given the commercial success of PDE5 inhibitors. In this regard, the conference includes discussion of the role of different PDEs and the therapeutic utility of inhibitors in cardiovascular disease, schizophrenia, mood disorders and neurodegenerative conditions such as Alzheimer disease. The meeting provides an important and needed opportunity to review the most recent developments in the field and aims to inform on the direction of research in this area for the next two years.