A mere 21 human phosphodiesterase (PDE) genes are responsible for modulating cellular levels of cAMP and cGMP in response to stimuli. Considering the importance of cAMP and cGMP to disparate physiological functions including visual response, smooth muscle relaxation, platelet aggregation, immune response, and cardiac contractibility, perhaps the 200 or more splice isoforms of PDE genes also play a major functional role. We profiled the human PDEs across 25 tissue samples using splice sensitive oligonucleotide microarrays containing probes for exons and exon-exon junctions. Our results suggest that PDEs exhibit tissue-specific differences in expression, as demonstrated by the high expression of PDE4B in skeletal muscle. At the splice variant level, the majority of PDE genes-notably 1A, 1C, 2A, 4C, 4D, 5A, 7A, 8A, 8B, 9A, 10A, and 11A-exhibited tissue-specific splicing with potential functional implications for PDE biology. This work validates expression of many EST transcripts, and confirms and expands on published findings based on PCR and cloning, illuminating some of the complexity of cAMP and cGMP processing. (c) 2006 Elsevier Inc. All rights reserved.