Experimentation in mesocosms is arguably the single most powerful approach to obtain a mechanistic quantitative understanding of ecosystem-level impacts of stressors in complex systems, especially when embedded in long-term observations, theoretical models and experiments conducted at other scales. AQUACOSM builds on an established European network of mesocosm research infrastructures (RI), the FP7 Infra project MESOAQUA (2009-2012), where 167 users successfully conducted 74 projects. AQUACOSM greatly enhances that network on pelagic marine systems in at least 3 ways: first by expanding it to 10 freshwater (rivers and lakes), 2 brackish and 2 benthic marine facilities, and by involving 2 SMEs and reaching out to more, thereby granting effective transnational access to world-leading mesocosm facilities to >340 users on >11500 days; second, by integrating scattered know-how between freshwater and marine RI; and third, by uniting aquatic mesocosm science in an open network beyond the core consortium, with industry involved in an ambitious innovation process, to promote ground-breaking developments in mesocosm technology, instrumentation and data processing. A new dimension of experimental ecosystem science will be reached by coordinated mesocosm experiments along transects from the Mediterranean to the Arctic and beyond salinity boundaries. These efforts will culminate in a joint research activity (JRA) to assess aquatic ecosystem responses across multiple environmental gradients to a selected climate-related key stressor with repercussions for ecosystem services. Overall, AQUACOSM will fill a global void by forging an integrated freshwater and marine research infrastructure network. Long-term sustainability is sought through assessing governance models based on science priorities and economic innovation opportunities. Linkages to and synergies with ESFRI RI and other large initiatives are ensured by AQUACOSM partners and Advisory Board members in those programs.