The Highveld region in South Africa is an important area for its food production for the nation, as 70% of country's cereal crops and 90% of the commercially grown maize is cultivated there. The sustainability of these agro-ecosystems is, therefore, of vital importance for the nation's food security. The western part of the Highveld is characterised by relatively low mean annual precipitation (MAP) and highly variable yields, and while rainfall increases towards the east, inter-annual yield variability remains high. Variability of yields is already a concern for agro-ecosystems and it is hypothesised that it could be exacerbated by future climate changes. A sustainability framework was used to assess the sustainability agro-ecosystems under plausible future climate scenarios. Three Quaternary Catchments were assessed ranging from relatively dry (MAP 432 mm) to relatively moist (MAP 903 mm). A sensitivity analysis of plausible scenarios was performed with incremental increases in temperature by 1, 2 or 3 ¡C, increases/decreases of rainfall by 10% and a doubling of pre-industrial atmospheric CO2 concentrations to 555 ppmv. From the present and nine plausible future climate scenarios which were modelled using CERES-Maize over a 44-year period, it is shown that climatic changes could have major negative effects on the already drier western, and therefore more vulnerable, areas of the South African Highveld. An increase in temperature increases the variability of yields in the relatively moist Piet Retief area (MAP 903 mm), while at the more sub-humid Bothaville, with a MAP of only 552 mm, the inter-annual variability remains the same but mean yield over 44 seasons is reduced by 30%. A simulated increase in temperature coupled with a doubling of CO2 increases the rate of soil organic nitrogen depletion from the agro-ecosystem. Therefore, long-term perspectives in regard to human well-being and ecological integrity need to be applied to policies and actions for sustainability of both commercial and smallholder agro-ecosystems, particularly, in the western Highveld.