Pierce's disease, caused by the bacterium Xylella fastidiosa, is one of the most devastating diseases of cultivated grape, currently restricted to the Americas. To test the long-standing hypothesis that Pierce's disease results from pathogen-induced drought stress, we used the Affymetrix Vitis GeneChip to compare the transcriptional response of Vitis vinifera to Xylella infection, water deficit, or a combination of the two stresses. The results reveal a redirection of gene transcription involving 822 genes with a minimum twofold change (P < 0.05), including the upregulation of transcripts for phenylpropanoid and flavonoid biosynthesis, pathogenesis-related proteins, abscisic acid- and jasmonic acid-responsive biosynthesis, and downregulation of transcripts related to photosynthesis, growth, and nutrition. Although the transcriptional response of plants to Xylella infection was largely distinct from the response of healthy plants to water stress, we find that 138 of the pathogen-induced genes exhibited a significantly stronger transcriptional response when plants were simultaneously exposed to infection and drought stress, suggesting a strong interaction between disease and water deficit. This interaction between drought stress and disease was mirrored in planta at the physiological level for aspects of water relations and photosynthesis and in terms of the severity of disease symptoms and the extent of pathogen colonization, providing a molecular correlate of the classical concept of the disease triangle in which environment impacts disease severity.