This book constitutes the refereed proceedings of the 21st International Conference on Intelligent Tutoring Systems, ITS 2025, held in Alexandroupolis, Greece, during  June 2–6, 2025.The 21 full papers, 27 short papers and 5 posters included in this book were carefully reviewed and selected from 67 submissions.  The papers are organized in the following topical conference tracks: Part I: Generative Tutoring Systems. The goal of this part is to show how new techniques inspired by artificial intelligence (AI) and new methods in education can improve learning, teaching, and generate the capacity for knowledge acquisition and much more. Part II: Application areas, environments, and techniques for AI systems. This part shows the progress of research investigating the different application areas (such as education, health), techniques (such as neural networks, data mining, natural language processing) and environments (such as games, virtual reality, cognitive robots) for effective AI systems.