This book constitutes the refereed proceedings of the 15th International Conference on Computational Methods in Systems Biology, CMSB 2017, held in Darmstadt, Germany, in September 2017. The 15 full papers, 4 tool papers and 4 posters presented together with 1 invited talk were carefully reviewed and selected from 41  regular paper submissions. Topics of interest include formalisms for modeling  biological processes; models and their biological applications; frameworks for model verication, validation, analysis, and simulation of biological systems; high-performance computational systems biology and parallel implementations; model inference from experimental data; model integration from biological databases; multi-scale modeling and analysis methods; and computational approaches for synthetic biology.