Systemic acquired resistance (SAR) is a plant immune response to pathogen attack. Recent evidence suggests that plant immunity involves regulation by chromatin remodeling and DNA methylation. We have investigated whether SAR can be inherited epigenetically following disease pressure by Pseudomonas syringae pv. tomato DC3000 (PstDC3000). Compared to progeny from control-treated Arabidopsis (C1), progeny from PstDC3000-inoculated Arabidopsis (P1) were primed to activate salicylic acid (SA)-inducible defense genes and were more resistant to the (hemi-)biotrophic pathogens Hyaloperonospora arabidopsidis and PstDC3000. This trans-generational SAR was sustained over one stress-free generation, indicating an epigenetic basis of the phenomenon. Furthermore, P1 progeny displayed reduced responsiveness of jasmonic acid (JA)-inducible genes and enhanced susceptibility to the necrotrophic fungus Alternaria brassicicola. This shift in SA- and JA-dependent gene responsiveness was not associated with changes in corresponding hormone levels. Instead, chromatin-immunoprecipitation analyses revealed that SA-inducible promoters of PR-1, WRKY6 and WRKY53 in P1 plants are enriched with acetylated histone H3 at lysine9, a chromatin mark associated with a permissive state of transcription. Conversely, the JA-inducible PDF1.2 promoter showed increased H3 triple-methylation at lysine27, a mark related to repressed gene transcription. P1 progeny from the defense regulatory mutant npr1-1 failed to develop trans-generational defense phenotypes, demonstrating a critical role for NPR1 in expression of trans-generational SAR. Furthermore, the drm1drm2cmt3 mutant that is affected in non-CpG DNA methylation mimicked the trans-generational SAR phenotype. Since PstDC3000 induces DNA hypomethylation in Arabidopsis, our results suggest that trans-generational SAR is transmitted by hypomethylated genes that direct priming of SA-dependent defenses in following generations.