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A current frontier in plant biology is to uncover the genes and gene variants that explain phenotypic diversity. However, it becomes clear that phenotypic variation often does not reflect the cumulative effect from individual gene mutations. This deviation is due to epistasis, the interactions between alleles, which is often unpredictable and quantitative in effect. In tomato, breeding with a mutation that improves fruit harvesting frequently results in excessive flowering and reduced fertility due to interaction with a cryptic variant in a homologous gene. We found that recently evolved copy number variants enabled breeders to neutralize negative epistasis on yield. By dissecting the mechanisms by which these copy number variants restored normal flowering and fertility, we devised strategies that use genome editing to predictably improve harvesting. Using additional traits and developmental pathways that were major targets of selection during tomato domestication and diversification, we now investigate how epistasis determines the effect of genetic variation on quantitative trait variation. Advancing our basic understanding of epistasis in crops can reveal new principles and approaches to engineer targeted improvements in agriculture.