Although developmentally regulated disease resistance has been observed in a variety of plant-pathogen interactions, the molecular basis of this phenomenon is not well understood. Arabidopsis thaliana ecotype Columbia-0 (Col-0) expresses a developmentally regulated resistance to Hyaloperonospora parasitica isolate Emco5. Col-0 seedlings support profuse mycelial growth and asexual spore formation in the cotyledons. In contrast, Emco5 growth and reproduction is dramatically (but not completely) restricted in the first set of true leaves. Subsequent leaves exhibit progresssively increased resistance. This adult resistance is strongly suppressed by expression of the salicylic acid-degrading transgene NahG and by loss-of-function mutations in the defense-response regulators PAD4, NDR1, RAR1, PBS3, and NPR1. In contrast to Col-0, the Wassilewskija-0 (Ws-0) ecotype supports profuse growth of Emco5 at all stages of development. Gene-dosage experiments and segregation patterns indicate that adult susceptibility in Ws-0 is incomepletely dominant to adult resistance in Col-0. Genetic mapping in a Col x Ws F2 population revealed a major locus on the bottom arm of chromosome 5, which we named RPP31. Analysis of T-DNA insertion lines indicated that the Columbia allele of RPP8, though tightly linked to RPP31, is not necessary for adult resistance.