Invasive stands of Prosopis (mesquite) cover over 6 million ha of South Africa and could invade over 56 million ha. These invasive stands have major impacts on biodiversity, local livelihoods and ecosystem services. We applied several methods to develop an objective basis for a national strategy to prioritise and guide the management of Prosopis. Decision trees were used for assigning different control objectives (prevention of spread to unoccupied areas, local eradication, containment and asset protection) to each of the 234 local municipalities in the country. Priority assets that require protection in densely invaded areas were identified, ranked and mapped (in order of importance: water source areas, biodiversity hotspots, and areas with high agricultural and rangeland potential). Available control methods were compared in terms of costs, effectiveness, and potential to create employment. Biological control and more mechanised approaches were identified as important and the role of control-through-utilisation requires urgent research. Scenario development suggests that integrated control would be most effective. Strategic guidelines for improving the management of Prosopis were produced. These guidelines discuss key needs and objectives for management, targets, time frames, indicators and monitoring programs, research needs and spatially prioritized management areas. Although the strategy proposed in this paper is specific to Prosopis in South Africa, the principles will be useful in other regions where Prosopis species are invasive, and more generally for other widespread invasive tree taxa. Keywords: Alien tree, Biological invasions, Ecosystem services, Multi-criteria decision making, Natural resource management, Strategic planning and management, Tree invasions.