Molecular biological methods including genomic and proteomic approaches hold a specific promise to provide new insights into the stress physiology of corals. However, to fully exploit the power of these techniques, aquarium setups are required that allow biological assays under tightly controlled laboratory conditions. Here, details are provided about the successful development of a closed coral mesocosm at the National Oceanography Centre, Southampton. The system can be operated without access to natural seawater and allows long-term observations and experimental studies of reef corals. The individual experimental tanks allow the corals to be exposed, for example, to different light and/or temperature conditions without the need to disconnect them from the system.