The root-to-soil delivery of specialized plant metabolites, which shape the rhizosphere microbiome and thereby affect crop fitness, occurs via root-plant transporters. This study demonstrated that cucurbitacins in cucurbit plants are secreted to the soil by MATE proteins, selectively enriching for two bacterial genera, Enterobacter and Bacillus, and this, in turn, leads to robust resistance against the soil-borne wilt fungal pathogen, Fusarium oxysporum.