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Recently, many new approaches, study designs, and statistical and analytical methods have emerged for studying gene-environment interactions (G×Es) in large-scale studies of human populations. There are opportunities in this field, particularly with respect to the incorporation of -omics and next-generation sequencing data and continual improvement in measures of environmental exposures implicated in complex disease outcomes. In a workshop called "Current Challenges and New Opportunities for Gene-Environment Interaction Studies of Complex Diseases," held October 17-18, 2014, by the National Institute of Environmental Health Sciences and the National Cancer Institute in conjunction with the annual American Society of Human Genetics meeting, participants explored new approaches and tools that have been developed in recent years for G×E discovery. This paper highlights current and critical issues and themes in G×E research that need additional consideration, including the improved data analytical methods, environmental exposure assessment, and incorporation of functional data and annotations.