In contrast to protein-coding sequences, the significance of variation in non-coding DNA in human disease has been minimally explored. A great number of recent genome-wide association studies suggest that non-coding variation is a significant risk factor for common disorders, but the mechanisms by which this variation contributes to disease remain largely obscure. Distant-acting transcriptional enhancers--a major category of functional non-coding DNA--are involved in many developmental and disease-relevant processes. Genome-wide approaches to their discovery and functional characterization are now available and provide a growing knowledge base for the systematic exploration of their role in human biology and disease susceptibility.