The Important Bird Areas (IBAs) network of BirdLife International aims to identify sites that are essential for the long-term conservation of the world’s avifauna. A number of global change events have the potential to negatively affect, either directly or indirectly, most bird species, biodiversity in general and associated ecological processes in these areas identified as IBAs. To assist conservation decisions, I assessed a suite of ten landscape scale anthropogenic pressures to 115 Important Bird Areas (IBAs) in South Africa, both those currently placing pressures on IBAs and those that constitute likely future vulnerability to transformation. These threats are combined with irreplaceability, a frequently used measure of conservation importance, to identify the suite of IBAs which are high priority sites for conservation interventions: those with high irreplaceability and are highly vulnerable to anthropogenic threats. A total of 22 (19%) of the South African IBAs are highly irreplaceable and are highly vulnerable to at least some of the pressures assessed. Afforestation, current and potential future patterns of alien plant invasions affect the largest number of highly irreplaceable IBAs. Only 9% of the area of highly irreplaceable IBAs is formally protected. A total of 81 IBAs (71%) are less than 5% degraded or transformed. This result, together with seven highly irreplaceable IBAs found outside of formally protected areas with lower human densities than expected by chance provides an ideal opportunity for conservation interventions. However, all the pressures assessed vary geographically, with no discernible systematic pattern that might assist conservation managers to design effective regional interventions. Furthermore, I used the newly emerging technique of ensemble forecasting to assess the impact of climate change on endemic birds in relation to the IBAs network. I used 50 endemic species, eight bioclimatic envelope models, four climate change models and two methods of transformation to presence or absence, which essentially creates 2400 projections for the years 2070-2100. The consensual projection shows that climate change impacts are very likely to be severe. The majority of species (62%) lose climatically suitable space and 99% of grid cells show species turnover. Five species lose at least 85% of climatically suitable space. The current locations of the South African Important Bird Areas network is very likely ineffective to conserve endemic birds under climate change along a “business a usual” emissions scenario. Many IBAs show species loss (41%; 47 IBAs) and species turnover (77%; 95 IBAs). However, an irreplaceability analysis identified mountainous regions in South Africa as irreplaceable refugia for endemic species, and some of these regions are existing IBAs. These IBAs should receive renewed conservation attention, as they have the potential to substantially contribute to a flexible conservation network under realistic scenarios of climate change. Considering all the global change threats assessed in this study, the Amersfoort-Bethal-Carolina District and the Grassland Biosphere Reserve (IBA codes: SA018; SA020) are the key IBAs in South Africa for conservation prioritisation.