Examining patterns of molecular genetic variation in both modern-day and ancient humans has proved to be a powerful approach to learn about our origins. Rapid advances in DNA sequencing technology have allowed us to characterize increasing amounts of genomic information. Although this clearly provides unprecedented power for inference, it also introduces more complexity into the way we use and interpret such data. Here, we review ongoing debates that have been influenced by improvements in our ability to sequence DNA and discuss some of the analytical challenges that need to be overcome in order to fully exploit the rich historical information that is contained in the entirety of the human genome.