This book constitutes the refereed proceedings of the 5th IFIP TC 5, TC 12, WG 8.4, WG 8.9, WG 12.9 International Cross-Domain Conference, CD-MAKE 2021, held in virtually in August 2021. The 20 full papers and 2 short papers presented were carefully reviewed and selected from 48 submissions. The cross-domain integration and appraisal of different fields provides an atmosphere to foster different perspectives and opinions; it will offer a platform for novel ideas and a fresh look on the methodologies to put these ideas into business for the benefit of humanity.