The powdery mildew resistance genes RPW8.1 and RPW8.2 from Arabidopsis differ from the other isolated plant resistance (R) genes in their predicted protein domains and their resistance spectrum. The two homologous RPW8 genes encode small proteins featuring a predicted amino-terminal transmembrane anchor domain and a coiled-coil domain and confer resistance to a broad spectrum of powdery mildews. Here, we show that Arabidopsis plants expressing the RPW8 genes have enhanced resistance to another biotrophic pathogen, Hyaloperonospora parasitica, raising the possibility that the RPW8 genes may function to enhance salicylic-acid-dependent basal defenses, rather than as powdery-mildew-specific R genes. When overexpressed from their native promoters, the RPW8 genes confer enhanced resistance to the Cauliflower mosaic virus, but render plants more susceptible to the necrotrophic fungal pathogens Alternaria and Botrytis spp. Furthermore, we show that the RPW8 proteins appear to be localized to the endomembrane system, overlapping with the endoplasmic reticulum–associated small GTPase SAR1, and accumulate to higher levels in response to application of exogenous salicylic acid, one of the signaling molecules of plant defense.