Plants continuously encounter various environmental stresses and use qualitative and quantitative measures to resist pathogen attack. Qualitative stress responses, based on monogenic inheritance, have been elucidated and successfully used in plant improvement. By contrast, quantitative stress responses remain largely unexplored in plant breeding, due to complex polygenic inheritance, although hundreds of quantitative trait loci for resistance have been identified. Recent advances in metabolomic and proteomic technologies now offer opportunities to overcome the hurdle of polygenic inheritance and identify candidate genes for use in plant breeding, thus improving the global food security. In this review, we describe a conceptual background to the plant–pathogen relationship and propose ten heuristic steps streamlining the application of metabolo-proteomics to improve plant resistance to biotic stress.