Achieving sustainable food security is a critical goal for smallholder farmers in mountainous regions around the world. In the 40,000 km² Maloti–Drakensberg mountains (South Africa and Lesotho), one of the important mountain ranges of southern Africa, farmers are directly dependent on natural resources. Natural resource management is currently unsustainable, driving landscape degradation and entrenching poverty cycles. Through a comprehensive literature review, we explore the current status of knowledge, opportunities, and agriculture-dependent natural resource sustainability in the Maloti–Drakensberg, and outline the priorities for future research in mountain agriculture in southern Africa. The Maloti–Drakensberg has diverse land tenure systems and climatic heterogeneity that together determine farming practices. Agropastoralism is the predominant agricultural practice, occupying 79% of the land, because of the natural grass-dominated vegetation. Despite decades of concern, the sustainable management of communal rangeland remains elusive. Arable cropping is practiced on 12% of the land at subsistence levels, while game farming contributes a small amount to local revenues. A multipronged research approach is needed to understand the complex social–ecological issues around soil degradation and sustainable utilization of the limited agricultural natural resources base. Innovative and adaptive strategies that take into account local and indigenous knowledge, mitigate soil degradation, and enhance water and rangeland conservation are needed to promote sustainable food production in the Maloti–Drakensberg.