The integration of applied intelligence with software has been an essential enabler for science and the new economy, creating new possibilities for a more reliable, flexible and robust society. But current software methodologies, tools, and techniques often fall short of expectations, and are not yet sufficiently robust or reliable for a constantly changing and evolving market. This book presents the proceedings of SoMeT_22, the 21st International Conference on New Trends in Intelligent Software Methodology Tools, and Techniques, held from 20 - 22 September 2022 in Kitakyushu, Japan. The SoMeT conference provides a platform for the exchange of ideas and experience in the field of software technology, with the emphasis on human-centric software methodologies, end-user development techniques, and emotional reasoning for optimal performance. The 58 papers presented here were each carefully reviewed by 3 or 4 referees for technical soundness, relevance, originality, significance and clarity, they were then revised before being selected by the international reviewing committee. The papers are arranged in 9 chapters: software systems with intelligent design; software systems security and techniques; formal techniques for system software and quality assessment; applied intelligence in software; intelligent decision support systems; cyber-physical systems; knowledge science and intelligent computing; ontology in data and software; and machine learning in systems software. The book assembles the work of scholars from the international research community to capture the essence of the new state-of-the-art in software science and its supporting technology, and will be of interest to all those working in the field.