Biomedical research increasingly depends on big data analysis and large-scale simulation. In 2009, the University of Chicago's Biological Sciences Division identified computational biomedicine as its major strategic focus for research, recruitment and strategic investment. The centerpiece of this initiative was the acquisition of Beagle-1, an 18,000-core, 600 TB supercomputer that ranked among the world's most powerful machines dedicated to biological and medical research. Since its debut in early 2011, more than 300 researchers from 89 projects have used Beagle-1, utilizing over 300 million core-hours of computing time. With Beagle-1, scientists pushed forward the frontiers of research on cancer, neuroscience, genetics, cardiovascular disease, microbiology, drug design, and other areas. Work conducted on Beagle-1 also sparked the emergence of a vibrant computational biomedicine community on the University Chicago campus and across the Chicago region, where faculty, post-docs, students and staff benefit from frequent workshops, seminars and educational opportunities. The surge in demand for biomedical supercomputing concomitant with Beagle-1 approaching the end of its life necessitates the acquisition of a new, more powerful resource: Beagle-2, a 23,808-core, 1.3 petabyte Cray XE6 system. This major upgrade will increase computational and big data storage capabilities by two fold while also delivering service for researchers through 2017. An estimated 150 million core hours per year for this system can already be filled by active, NIH-funded projects studying the genetics of cancer and myopathies, the microbiology of the human gut and its relationship to disease, the use of medical images to create personalized treatments for cancer, the cell biology of Alzheimer's disease, the evolutionary origins of language centers in the brain, and much more. Beagle-2 will allow the University of Chicago to further develop a biomedical computing facility that enhances research and patient care, trains the next generation of biomedical computing experts, enables collaboration by researchers across the Chicago region and beyond, and produces transformative new methods, software tools, and data products that will advance biomedical research on a global scale.