Focusing on the case of foot and mouth disease (FMD) in southern Africa – and specifically Botswana, Namibia, South Africa and Zimbabwe – this paper explores the economic, social and political trade-offs arising from different scenarios for gaining market access and managing and controlling FMD in support of beef production in southern Africa. A central question is: does the current approach, premised on the ability to separate a ‘disease free’ commercial sector from areas at high risk of FMD outbreaks because of the presence or proximity of wildlife (African buffalo particularly) through strictly enforced protection (formerly known as ‘buffer’) zones and movement control, make sense given new contexts and challenges? Are there other alternatives that benefit a wider group of producers, ensure food-safe trade, and are easier to implement, yet maintain access to important export markets and so foreign exchange revenues? Following an examination of the new contexts of disease dynamics and livestock trade in southern Africa, the paper explores a series of scenarios for market access including: trade with the European Union; direct exports to large retailers; export to emerging markets, particularly Asia; regional trade in southern Africa and domestic urban and rural markets. Given this assessment, the paper then asks: what makes most sense for the control and management of FMD in southern Africa?