Over the past three decades, marine resource management has shifted conceptually from top-down sectoral approaches towards the more systems-oriented multi-stakeholder frameworks of integrated coastal management and ecosystem-based conservation. However, the successful implementation of such frameworks is commonly hindered by a lack of cross-disciplinary knowledge transfer, especially between natural and social sciences. This review represents a holistic synthesis of three decades of change in the oceanography, biology and human dimension of False Bay, South Africa. The productivity of marine life in this bay and its close vicinity to the steadily growing metropolis of Cape Town have led to its socio-economic significance throughout history. Considerable research has highlighted shifts driven by climate change, human population growth, serial overfishing, and coastal development. Upwelling-inducing winds have increased in the region, leading to cooling and likely to nutrient enrichment of the bay. Subsequently the distributions of key components of the marine ecosystem have shifted eastward, including kelp, rock lobsters, seabirds, pelagic fish, and several alien invasive species. Increasing sea level and exposure to storm surges contribute to coastal erosion of the sandy shorelines in the bay, causing losses in coastal infrastructure and posing risk to coastal developments. Since the 1980s, the human population of Cape Town has doubled, and with it pollution has amplified. Overfishing has led to drastic declines in the catches of numerous commercially and recreationally targeted fish, and illegal fishing is widespread. The tourism value of the bay contributes substantially to the country’s economy, and whale watching, shark-cage diving and water sports have become important sources of revenue. Compliance with fisheries and environmental regulations would benefit from a systems-oriented approach whereby coastal systems are managed holistically, embracing both social and ecological goals. In this context, we synthesize knowledge and provide recommendations for multidisciplinary research and monitoring to achieve a better balance between developmental and environmental agendas.