The two-volume proceedings set LNCS 16605 and 16606 constitutes the refereed main proceedings of the 21st International Conference on Design Science Research in Information Systems and Technology, DESRIST 2026, which was held in Münster, Germany, during June 8–10, 2026. Given the large number of high-quality contributions, the 2026 proceedings are published in three volumes: LNCS 16605 and 16606 as main proceedings include all accepted full papers, while LNCS 16607 contains all accepted Prototypes and Research-in-Progress Proceedings papers. DESRIST 2026 received a total of 231 submissions across all tracks and formats. The 48 full papers included in these main proceedings were carefully reviewed and selected from 108 full research paper submissions. The papers presented in LNCS 16605 and 16606 as main proceedings are organized in the following topical sections:Part I : Design for Better Futures: Beyond the Science of the Artificial (Theme Track)

“From Insight to Impact” (General Track)

The Future of Financial Services; Future of Data-Driven and AI-Enabled Design; Future of Healthcare and Wellbeing. Part II : Future of Design and Entrepreneurship; Future of Responsible and Sustainable Design; Future of Design Science Education; Future of Design Science Methodology; Future of Ecosystems for Design Science Research.