I will discuss the use of genomic technologies - mostly ultrahigh-throughput DNA sequencing - to study normal human biology and to determine what goes wrong when we have disease. First I will discuss using genomics to study human genetics, where we can now identify all of the allelic variation, both inherited from parents and acquired, as in cancer, that is present in a person's DNA. The sequencing technologies can be used to target particular regions of the genome, and I will show how this can be used to measure the repertoire of T cells and antibody-producing B cells in the peripheral blood for healthy individuals as well as people affected with a disease. Inexpensive and accurate whole genome sequencing is now available, and I will discuss its use in identifying the causes of intellectual and development disorders in children with heretofore undiagnosed phenotypes. Secondly, I will discuss how we use DNA sequencing in functional genomics, including measurements of RNA, DNA methylation and protein:DNA interactions on a genome-wide scale. These methods are applied to a wide variety of cell lines and tissues as part of the ENCODE Project, as well as to cohorts of individuals with a variety of diseases, particularly cancer. Finally, I will show how we use these approaches to identify responders and non-responders in drug trials for breast cancer. Learning Objectives: 1. To understand how DNA sequencing allows not only genetic variation to be determined on an unprecedented scale, but also to understand its applications in a wide variety of functional genomics measurements. In addition, I hope that participants will learn how integrating these different types of data provides power to understand biology and disease than any one approach alone can provide. 2. To learn how genomic discoveries can be used to provide predictive biomarkers for disease and differential responses to treatments.