ChallengeEU unites 9 small to medium-sized universities across Europe (83,000 students, 9,000 staff). The Alliance seeks to create responsive innovation ecosystems in 3 rural, 3 peripheral, and 3 urban regions, impacting 25 million citizens in the ChallengeEU Higher Education area. Moreover, 80 associated partners from all areas of the Quadruple Helix will act as multipliers of the Alliance’s methodologies within and across regions. Striving to initiate a shift from topic-driven towards challenge-and-impact-driven research and education, ChallengeEU introduces a transformative innovation model that other European regions can adopt: Multi-Actor Research & Knowledge Exchange Teams (M.A.R.K.E.T.s) enable sustainable collaboration spaces. Implementing multi-stakeholder M.A.R.K.E.T. SQUAREs and strategic M.A.R.K.E.T. MEETUPs across regions, ChallengeEU aligns with European innovation strategies. The Alliance addresses 3 Smart Specialisation Areas (Smart Digitalisation, Sustainable Futures, and Health & Wellbeing) and their regional challenges. Solutions will be co-created, fostering responsibility, entrepreneurship, and collaboration skills through the ChallengeEU ACADEMY, with its pillars TEACHING, TALENT and TRAINING. ChallengeEU involves stakeholders of the Quadruple Helix through at least 108 public engagement activities and 100 M.A.R.K.E.T. SQUARE events. The Alliance initiates at least 36 start-ups and addresses around 10,000 visitors to collaborate on the digital M.A.R.K.E.T.place. The Alliance develops 18 shared challenge-based learning opportunities involving stakeholders, introduces at least 16 micro-credential courses for students and lifelong learners, strives for 3 joint programmes and 1 pilot joint degree. The ChallengeEU online repository will reach ~20,000 students and academic staff. ODEI awareness is linked to all activities. The Alliance aims to achieve 50% participation in mobility opportunities among students and staff.