Innovation has significantly contributed to the growth and development of society in the 20th century. In addition to innovation, sustainability is another topic widely recognized as fundamental for a company’s competitiveness, regardless of the industry it belongs to. Even if sustainability has often focused on environmental concerns, it is a three dimensions concept, namely: environmental, economic and social (World Commission on Environment and Development, 1987). Thus, also in developing innovation, companies have to take into account the three above-mentioned dimensions. Moreover, innovation is often considered a comprehensive system that interacts closely with the surrounding environment, and the literature refers to this system with the term “innovation ecosystem”. A new challenge for innovation ecosystems is represented by the demands for sustainable development in environmental, economic and social dimensions. Notwithstanding the growing interest in these topics, the extant literature is still fragmented, and a comprehensive analysis is missed. To address this gap, this paper aims to propose a conceptual framework. In order to reach this objective, we adopted a two-steps methodology (i.e., a literature review based on a bibliometric and a keywords analysis approach, and exploratory case studies). The results of the first phase showed that companies’ investments in R&D, the type of innovation developed, the issue of sustainability and the degree of “openness” are closed linked elements. These theoretic findings have been validated by a multiple case study conducted on a sample of 26 companies operating in different industries. As a further result, several research avenues are reported as distilled from the analysis.