The term next-generation sequencing is almost a decade old, but it remains the colloquial way to describe highly parallel or high-output sequencing methods that produce data at or beyond the genome scale. Since the introduction of these technologies, the number of applications and methods that leverage the power of genome-scale sequencing has increased at an exponential pace. This review highlights recent concepts, technologies, and methods from next-generation sequencing to illustrate the breadth and depth of the applications and research areas that are driving progress in genomics. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 17 is August 31, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.