Cultural heritage is recognized as a powerful driver of sustainable development in cities and regions. The adaptive reuse and regeneration of cultural and natural heritage can become a driver of jobs creation, as demonstrated by many experiences. At the same time, cultural heritage adaptive reuse can involve communities in innovative and unexpected ways, generating multiple positive impacts in the territories and boosting a more sustainable, resilient, and equitable development model to finally create cities of opportunities connecting culture and innovation. This chapter aims to share the experience of the Horizon 2020 CLIC project in developing innovative circular business models for cultural heritage adaptive reuse, through the selection and training of start-ups during the entrepreneurial event of the CLIC Startup Competition in 2020 and subsequent mentoring programme. The chapter presents virtuous case studies as examples of successful social entrepreneurship and circular business model of heritage reuse and regeneration. A critical reflection on the role of social entrepreneurship and innovative business models for circular cultural heritage adaptive reuse is provided based on the experience of the project.