Previous reports on the model nonhost resistance interaction between Fusarium solani f. sp. phaseoli and pea endocarp tissue have described the disease resistance-signaling role of a fungal DNase1-like protein. The response resulted in no further growth beyond spore germination. This F. solani f. sp. phaseoli DNase gene, constructed with a pathogenesis-related (PR) gene promoter, when transferred to tobacco, generated resistance against Pseudomonas syringe pv. tabaci. The current analytical/theoretical article proposes similar roles for the additional nuclear and mitochondrial nucleases, the coding regions for which are identified in newly available fungal genome sequences. The amino acid sequence homologies within functional domains are conserved within a wide array of fungi. The potato pathogen Verticillium dahliae nuclease was divergent from that of the saprophyte, yeast; however, the purified DNase from yeast also elicited nonhost defense responses in pea, including pisatin accumulation, PR gene induction, and resistance against a true pea pathogen. The yeast mitochondrial DNase gene (open reading frame) predictably codes for a signal peptide providing the mechanism for secretion. Mitochondrial DNase genes appear to provide an unlimited source of components for developing transgenic resistance in all transformable plants.