We isolated previously several Arabidopsis thaliana mutants with constitutive expression of the early microbe-associated molecular pattern-induced gene ATL2, named eca (expresión constitutiva de ATL2). Here, we further explored the interaction of eca mutants with pest and pathogens. Of all eca mutants, eca2 was more resistant to a fungal pathogen (Botrytis cinerea) and a bacterial pathogen (Pseudomonas syringae) as well as to a generalist herbivorous insect (Spodoptera littoralis). Permeability of the cuticle is increased in eca2; chemical characterization shows that eca2 has a significant reduction of both cuticular wax and cutin. Additionally, we determined that eca2 did not display a similar compensatory transcriptional response, compared with a previously characterized cuticular mutant, and that resistance to B. cinerea is mediated by the priming of the early and late induced defense responses, including salicylic acid- and jasmonic acid-induced genes. These results suggest that ECA2-dependent responses are involved in the nonhost defense mechanism against biotrophic and necrotrophic pathogens and against a generalist insect by modulation and priming of innate immunity and late defense responses. Making eca2 an interesting model to characterize the molecular basis for plant defenses against different biotic interactions and to study the initial events that take place in the cuticle surface of the aerial organs.