Natural History Collections (NHC) are an essential part of the world’s natural and cultural capital. They stand for collective scientific efforts of more than 500 years. European institutions maintain together 55% of the global NHCs, or more than 1.5 billion specimens. Eighteen major NHC organisations in Europe, holding almost 400 m biological, geological and paleontological specimens, have joined forces to create SYNTHESYS, an integrated European infrastructure for researchers in the natural sciences. SYNTHESYS enhances accessibility to its NHC, supports (systematic) research on them, and promotes collection management activities to ensure their long-term maintenance, through three main strands of work (Transnational Access, Joint Research Activities, Network Activities). Starting in 2004, SYNTHESYS has since received continuous European Commission funding to three interconnected projects. This clearly demonstrates the significance assigned to NHC as a key research infrastructure by the Commission. During its three incarnations so far, >3,800 individual scientists have benefitted from SYNTHESYS support for their NHC-based research, which resulted in over 4,500 scientific outputs. I will present both research highlights and major activities of the collaborative work strands. The future of SYNTHESYS is leading towards the development of a pan-European NHC infractructure to be operated as a "Distributed System of Scientific Collections" (DiSSCo). This initiative is currently backed up by 18 national governments. It will increase quality and quantity of NHC research, facilitate new approaches to the study of natural diversity, but also open up for new uses of NHC targeted research on the societal challenges.