AbstractIt seems intuitive that disease risk is influenced by the interaction between inherited genetic variants and environ mental exposure factors; however, we have few documented interactions between variants and exposures. Advances in technology may enable the simultaneous measurement (i.e., on the same individuals in an epidemiological study) of mil-lions of genome variants with thousands of environmental Bexposome^factors, significantly increasing the number of possible factor pairs available for testing for the presence of interactions. The burden of analytic complexity, or sheer num-ber of genetic and exposure factors measured, poses a consid-erable challenge for discovery of interactions in population scale data. Advances in analytic approaches, large sample sizes, less conservative methods to mitigate multiple testing, and strong biological priors will be required to prune the search space to find reproducible and robust gene-by-environment interactions in observational data.