For the past century, Mendelian and multifactorial traits have existed at opposite ends of the disease spectrum in humans. Furthermore, the recent emphasis on genome-wide association studies for uncovering variants that underlie common diseases has risked deepening the divide - or has it? Four experienced human geneticists express their views on the changing landscape of human disease studies and the impact of new technologies and study designs on the age-old aim of connecting a genomic variant with its phenotypic consequences.