Pest-resistant crops are a cornerstone of integrated pest management and are especially vital for crop-pest systems where effective pesticides are not available or have undesirable externalities. However, breeding progress for pest resistance can be constrained by low heritability and a limited understanding of resistance mechanisms. Here I present integrative research to breed for resistance to the Cucurbitaceae-specialized Acalymma vittatum (striped cucumber beetle) in Cucurbita pepo (zucchini, summer squash) that draws on fundamental chemical ecology principles and plant genomics to directly address these challenges. First, it was established that Acalymma vittatum preference is defined by C. pepo population structure, where C. p. pepo is preferred over C. p. ovifera. I then characterized resistance mechanisms on the subspecies level. I found differences in defense induction within and between subspecies, and identified variation in foliar volatiles that may affect A. vittatum acceptance of host plants. In addition, inter-subspecific populations were developed to dissect the genetic and mechanistic basis of traits confounded by subspecies. I tested how cucurbitacins, bitter triterpenoids, affect A. vittatum preference in C. pepo agricultural systems. The key results were that cucurbitacin accumulation in specific tissues did not have plant-wide effects on A. vittatum preference, and cucurbitacin biosynthesis is tightly linked with developmental stage. In addition, inter-subspecific populations were used for phenotypic and genomic selection for non-preference, where genomic selection had moderate predictive ability. A central theme in this research is a critical understanding of which traits to phenotype in the context of a breeding program. For breeding goals that center on biotic interactions, this relies on weighing the value of resource-intensive mechanism discovery and application, and mechanism-blind applications that take advantage of genomic tools. The fulcrum of balancing these efforts is the predicted difference between the response to selection on biotic resistance traits directly or correlated response to selection on chemical traits. Overall, these tandem and complementary approaches are crucial in developing pest-resistant crops.