Despite the tremendous successes of genomic approaches to rare disease diagnosis, the majority of rare disease patients remain undiagnosed, and the majority of the genes underlying these diseases remain undiscovered. One of the most powerful resources for understanding the functional impact of human genetic variation is the distribution of naturally occurring genetic variation across the population. In this talk I'll describe the development of massive-scale resources of human genetic data, spanning exome and genome data from over 135,000 individuals, and the applications of these resources to improving diagnosis of rare disease, understanding the patterns of constraint against gene-disrupting variation, the penetrance of disease-causing variation, and the likely feasibility of specific genes as therapeutic drug targets.