Parasitic nematodes (e.g. Meloidogyne hapla) cause >; $100 billion loss of agricultural crops annually. Current approaches to pest control are often unsafe and ineffective. Thus, developing a pesticide with an increased selectivity, efficacy, and safety profile is a high priority for agriculture. Disruption of cyclic nucleotide metabolism in nematodes by inhibiting phosphodiesterase (PDE) activity has been shown to disrupt the life cycle of the roundworm C. elegans. We hypothesize that the PDEs present in parasitic nematodes may have amino acid differences in their drug binding sites that can be exploited to selectively target plant parasitic nematodes to disrupt their life cycle. We compiled a phylogenetically diverse set of amino acid sequences for the 11 vertebrate PDE sequences which were used to identify orthologs in nematode genomes (Caenorhabditis spp. and M. hapla) that correspond to vertebrate PDE families 1, 2, 3, 4, 8, and 10. Multiple sequence alignments of the catalytic domain identified 13 unanimous and multiple family‐specific sites. Analysis of known drug interaction sites of selective inhibitors of human PDE3 and PDE4 showed that ~80% of the residues responsible for drug stabilization in human PDEs are also present in M. hapla orthologs. This supports the idea that parasitic nematodes will be susceptible to disruption of their life cycle by PDE inhibitors. Supported by USDA Hatch grant NH00568.