Significance Susceptibility (S) genes are plant genes that facilitate pathogen infection. Inactivation of S genes has been considered a promising strategy to obtain broad-spectrum and durable resistance in crops. We characterized two orthologs of the Arabidopsis S gene DMR6 in tomato: SlDMR6-1 and SlDMR6-2 . We show that SlDMR6-1, but not SlDMR6-2, is associated with plant immunity. Remarkably, Sldmr6-1 mutants display enhanced resistance to bacterial, oomycete, and fungal pathogens. This phenotype correlates with increased levels of the defense hormone salicylic acid (SA) and enhanced transcriptional activation of plant immune responses. We also demonstrate that SlDMR6-1 and SlDMR6-2 convert SA into its inactive form, 2,5-DHBA, indicating that they play a role in SA homeostasis.