The last 20 years have been a remarkable era for biology and medicine. One of the most significant achievements has been the sequencing of the first human genomes, which has laid the foundation for profound insights into human genetics, the intricacies of regulation and development, and the forces of evolution. Incredibly, as we look into the future over the next 20 years, we see the very real potential for sequencing more than one billion genomes, bringing with it even deeper insights into human genetics as well as the genetics of millions of other species on the planet. Realizing this great potential, though, will only be achieved through the integration and development of highly scalable computational and quantitative approaches can keep pace with the rapid improvements to biotechnology. In this perspective, we aim to chart out these future technologies, anticipate the major themes of research, and call out the challenges ahead. One of the largest shifts will be in the training used to prepare the class of 2035 for their highly interdisciplinary world.