Leafhoppers (Homoptera: Cicadellidae) that feed on xylem fluid transmit numerous diseases incited by Xylella fastidiosa including Pierce's disease of grapevine, plum leaf scald, phony peach disease, citrus variegated chlorosis, and scorch diseases of many plant species. The most important leafhopper vector of X. fastidiosa in the southeastern United States is the glassy-winged sharpshooter, Homalodisca vitripennis. Despite the prevalence of Xylella-mediated diseases in the United States for over 100 years, there has been relatively little progress in disease control. The economic impact of X. fastidiosa on grapevine, citrus, peach, plum, and almond is in the hundreds of millions of dollars in terms of limiting geographic areas of potential cultivation, and lost production in areas of current cultivation. Both the leafhopper vectors and X. fastidiosa have extremely broad host ranges and are numerous and endemic in many temperate and subtropical locations. In this paper, we present an interdisciplinary perspective that integrates plant xylem chemistry, entomology, and plant pathology to provide a comprehensive "whole systems" approach to leafhopper vectors and diseases caused by X. fastidiosa.