Living shorelines that comprise oyster reefs within a mosaic of multiple coastal habitats can be a resilient and adaptive coastal protection alternative to conventional engineered structures. The success of an oyster reef living shoreline is based on the evolution of a stable base-substrate delivering initial coastal protection in the short-term, to the growth of a living oyster reef and associated habitats in the longer-term that can enhance protection along with other ecosystem services. The design of an oyster reef living shoreline therefore needs to integrate the biology and ecology of oysters with the engineering design of coastal structures that considers the influence on physical processes (i.e., hydrodynamics and sediment transport), requiring interdisciplinary efforts for such projects to be successful. “Reefense” is an innovative program established by the US Defense Advanced Research Project Agency (DARPA) to design and construct biogenic reef-based living shorelines from first principles integrating engineering, ecology, adaptive biology and techno-economics. Here, we use the example of the first 3 years of Reefense to illustrate an interdisciplinary approach to the design of oyster reef living shorelines with the aim of informing future development of global teams that can produce the research required to underpin large-scale implementation.