Abstract: Many areas of science and engineering have adopted simulation-based research as a novel tool for discovery and insight. The sustained performance growth in supercomputer performance allows ever more detailed models, which makes supercomputing nowadays also a viable tool for biology. However, the heterogeneity of biological systems challenges many aspects of supercomputing: intricate workflows are required for model generation, mathematical formulations are volatile, and memory requirements are demanding. At the same time, the weak scaling properties of many biological systems are enormous and therefore are a good match for today¹s massive parallelism, whereas the multiple time scales inherent to biological systems requires outside-the-box thinking. On the example of the European Human Brain Project challenges and opportunities for HPC are discussed.