Humans vary according to a plethora of traits, such as height, hair color, behavior, and susceptibility to disease. Both genetics (nature) and environment (nurture) contribute to this variation. Recent large-scale genetic studies have identified thousands of specific DNA variations in the human population that are associated with different traits. However, these studies do not answer a key question: By what means do most DNA variants alter cellular behavior and contribute to differences in specific traits, such as height? A trio of papers in this issue by Kasowski et al. on page 750 , Kilpinen et al. on page 744 , and McVicker et al. on page 747 provide a framework for exploring the mechanistic link between genetic and trait variation in the human population. Specifically, they find that DNA variants influence a layer of gene regulation called epigenetics through the sequence-specific activity of transcription factors.