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We present a novel way to select for highly polygenic traits. For millennia, humans have used observable phenotypes to selectively breed stronger or more productive livestock and crops. Selection on genotype, using single-nucleotide polymorphisms (SNPs) and quantitative trait loci (QTLs), is also now applied broadly in livestock breeding programs; however, selection on protein or mRNA expression markers have not been proved useful yet. Here we demonstrate the utility of protein markers to select for disease-resistant behaviour in the European honey bees (Apis melliferaL.). Robust, mechanistically-linked protein expression markers, by integrating cis and trans effects from many genomic loci, may overcome limitations of genomic markers to allow for selection. After three generations of selection, the resulting stock performed as well or better than bees selected using phenotype–based assessment of this trait, when challenged with disease. This is the first demonstration of the efficacy of protein markers for selective breeding in any agricultural species, plant or animal.Significance statementThe honey bee has been in the news a lot recently, largely because of world-wide die-offs due to the parasitic Varroa mite, which is becoming resistant to the chemical controls the bee industry uses. In this study, we show that robust expression biomarkers of a disease-resistance trait can be used, in an out-bred population, to select for that trait. After three generations of selection, the resulting stock performed as well or better than bees selected using the phenotypic best method for assessing this trait when challenged with disease. This is the first demonstration of an expression marker for selective breeding in any agricultural species, plant or animal. This also represents a completely novel way to select for highly polygenic traits.