We describe six Arabidopsis mutants, defining at least four loci, that spontaneously form necrotic lesions on leaves. Lesions resemble those resulting from disease, but occur in the absence of pathogen. In five mutants, lesion formation correlates with expression of histochemical and molecular markers of plant disease resistance responses and with expression of genes activated during development of broad disease resistance in plants (systemic acquired resistance [SAR]). We designate this novel mutant class Isd (for lesions simulating disease resistance response). Strikingly, four Isd mutants express substantial resistance to virulent fungal pathogen isolates. Isd mutants vary in cell type preferences for lesion onset and spread. Lesion formation can be conditional and can be induced specifically by biotic and chemical activators of SAR in Isd1 mutants.