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Downy mildews cause significant losses in many crops. These obligate oomycetes also serve as model pathogens for studying resistance and susceptibility to biotrophs in Arabidopsis and several well-characterized crop species. In this presentation, I will describe the complementary approaches we use to investigate the molecular mechanisms underlying disease development and potential intervention strategies. This includes studying pathogen effectors, the role of the microbiome in downy mildew disease, susceptibility genes and their associated trade-offs, and the genetic basis of quantitative resistance traits. I will highlight recent findings from our work on a diverse lettuce panel, which led to the cloning of the LNR receptor gene - a candidate for providing quantitative resistance against a broad group of pathogens that secrete NEP1-like proteins (NLPs). To foster discussion, I will conclude with perspectives on how insights into plant–pathogen interactions can be translated into breeding for durable disease resistance.