The 'famille nombreuse' of cyclic nucleotide phosphodiesterases, responsible for degrading the ubiquitous second messenger molecules, cAMP and cGMP, maintains its place as a major focus of interest for many research laboratories in both academia and industry. The increase in knowledge of the primary sequences, plus the availability of selective inhibitors, are rapidly improving our insight into the structure, regulation and function of these pivotal enzymes of cellular homeostasis. Here, Thomas Müller, Peter Engels and John Fozard focus on family 4 of the phosphodiesterases, which is of particular interest owing to both the number of genes (and splice variants) and the emergence of selective inhibitors, which are enabling the functional significance of these enzymes to be defined.