The Arabidopsis thaliana genome contains more than 200 rapidly evolved resistance (R)-like genes coding for nucleotide binding leucine-rich repeat (NB-LRR) and their related proteins. A dozen of them are shown to play key roles in plant responses to biotic attacks, and they need to be repressed in the absence of biotic stresses to prevent activation of defense responses that are usually detrimental to plant growth and development. Here, we show that the Arabidopsis BON1 and BON3 genes, two members of the evolutionarily conserved copine, are negative regulators of several R-like genes. At least four such genes of the Toll-interleukin-1 receptor-like (TIR)-NB-LRR or TIR-NB type were identified through their activities in triggering cell death in the absence of the BON1 and BON3 function and their natural variations between two Arabidopsis accessions, Col-0 and Ws-2. These so-named lesion cell death (LCD) genes contribute quantitatively to the phenotypes of enhanced defense response and cell death in the bon1bon3 mutant. Further, their activation in the bon1bon3 mutants appears to be through different regulatory modes, and BON1 and BON3 may repress the transcript accumulation or protein activities of these R-like genes.