The trans-boundary rivers of the Limpopo basin in southern Africa have tremendous social, economic and ecological values. These resources are limited and over-utilised and affected by multiple stressors. For sustainability, a balance between the use and protection of the rivers is urgently required. And to reach this balance suitable trans-boundary water resource management must be developed. The study aims to evaluate the socio-ecological consequences of altered flows and non-flow stressors associated with four alternative water resource use and protection scenarios, including the e-flows established in the study using the PROBFLO method. PROBFLO combines Relative-Risk Modelling and the use of Bayesian Network probability modelling to determine environmental flows (e-flows) and evaluate the risk of alternative flow scenarios. Presently the rivers of the Limpopo Basin that were perennial are now seasonal, and rivers that were seasonal rivers are now episodic. Many additional stressors including altered water quality, habitat alteration, alien invasive fauna and flora and disturbance to wildlife impacts have been characterised and shown to have a synergistic effect of the wellbeing of the water resources in the basin. While the e-flows have been established, can they be achieved? And what is the cost-benefit of implementing e-flows in the basin? Risk assessments can be used to characterise multiple stressors, and their synergistic effects to the provisioning, regulators, supporting and cultural services of rivers that we care about. These assessments can help us make good trade-off decisions between the use and protection of water resources for a sustainable future.