This book constitutes the refereed proceedings of the Second International Symposium on Mathematical and Computational Oncology, ISMCO 2020, which was supposed to be held in San Diego, CA, USA, in October 2020, but was instead held virtually due to the COVID-19 pandemic.The 6 full papers and 4 short papers presented together with 1 invited talk were carefully reviewed and selected from 28 submissions. The papers are organized in topical sections named: statistical and machine learning methods for cancer research; mathematical modeling for cancer research; general cancer computational biology; and posters.