This paper responds to the need in innovation research for conceptual clarity and solid theory on social innovation (SI). The paper conceptualizes SI as changing social relations, involving new ways of doing, knowing, framing and organizing, and theorizes transformative social innovation (TSI) as the process of SI challenging, altering, or replacing dominant institutions in a specific social-material context. Three advances towards TSI theory are proposed. First, we reflect epistemologically on the challenges of theory-building, and propose an appropriate research design and methodology. Middle-range theory is developed through iteration between theoretical insights and comparative empirical study of 20 transnational SI networks and about 100 associated initiatives. Second, we synthesize various innovation theories and social theories into a relational framework that articulates the distributed agency and institutional hybridization involved. Third, we formulate twelve propositions on the emergence of SI initiatives, on the development of SI ecosystems, on institutionalization processes, and on the historical shaping of SI. The paper ends with a critical assessment of the advances made, also identifying further challenges for TSI theory and practice.