A number of phosphodiesterases, some of which possess additional biological activities (e.g., antitumor, immunosuppressive, and so on), have been considered for use in targeted tumor therapy. We propose Deoxyribonuclease I (DNase I), a compact, monomeric enzyme, as a very attractive candidate for targeting to tumor cells. Only a small amount of enzyme targeted to a cell needs to enter the nucleus in order to degrade the chromosomal DNA, making a cell incapable of further replication. We describe preliminary data on the construction of a potent single-chain antibody (scFv) immunotoxin based on bovine pancreatic DNAse I. The use of a mammalian enzyme should be much less toxic and less immunogenic than current immunotoxins and may expand the current limits of immunotoxin therapy.