Individuals of a species respond differently to environmental perturbations, and the genetic makeup is largely responsible for the variation in responses. With the advent of new sequencing tools that made tremendous genomic information available in a given species , we now have an unprecedented opportunity to investigate phenotypic variation in adaptive traits governed by genotype by environment (G x E) and G x G interactions. Numerous genome-sequencing projects revealed that genetic variability in plant immune components is exceptional, reflecting complex defense strategies that plants employ. The extreme variation sometimes makes a fatal outcome. Hybrid necrosis is the best-known example of genetic incompatibility in plants, in which autoimmune responses are triggered by deleterious interactions of independently evolved immune alleles . We exploited genetic and genomic tools available in the model plant species Arabidopsis thaliana to systematically investigate intraspecific hybrid necrosis . The species-wide work identified hot spots for genetic incompatibilities in the genome, often in regions densely populated by Nucleotide-binding Leucine-rich (NLR) immune receptor genes with extreme polymorphisms. A particularly dangerous locus is a highly variable cluster of NLR genes, DANGEROUS MIX2 (DM2), which causes multiple, independent incompatibilities with genes that encode a range of biochemical functions, including other NLRs. Our findings suggest that deleterious interactions of immune components that are presumably at the front lines of host-pathogen co-evolution would limit the combinations of favorable disease resistance alleles accessible to plant genomes. This systems genetics work provides a unique platform to furtherinvestigate molecular mechanisms of immune receptor activation  and to dissect tradeoffs between immunity and growth in plants . In my talk, I will address topics on how genetics of speciation and genetic incompatibility contribute to mechanistic understanding of adaptation, how natural variation can be exploited to understand trait evolution, and how current knowledge gained from a model system shall be translated to improve breeding practices.