Climate change and the HIV/AIDS epidemic are two of the most critical long-term global challenges, especially for Africa and even more so Southern Africa. There is great concern that the poor will be unable to adapt to the impacts of climate variability and change while HIV/AIDS will exacerbate the impacts of such stressors and deepen the insecurities of many communities already affected by this disease. Studies that consider the interlinked effects of climate change and HIV/AIDS along with other multiple stressors are increasingly needed. This study, located in two rural communities in the Eastern Cape Province of South Africa, namely Lesseyton and Willowvale, assessed the responses of vulnerable households to the linked shocks and stressors of climate change and HIV/AIDS. This involved assessing, through household surveys, life history interviews and Participatory Learning and Action (PLA), the way in which multiple stressors interacted and affected vulnerable households, the way in which these households responded to and coped with such shocks and stressors, and the barriers which prevented them from coping and adapting effectively. Unemployment emerged as the dominant stress amongst households. The lack of development and having too few opportunities for employment has limited vulnerable households from being able to invest in assets, such as education or farming equipment. This, in combination with the impacts of increased food and water insecurity from recent drought, has created an extremely vulnerable environment for these households. They rely largely on two important safety-nets, namely social capital and the use of natural and cultivated resources; however the latter has been limited due to the impacts of water scarcity and an inability to farm. It was evident that there was little planned long-term adaptation amongst households and from government. Maladaptive short-term coping strategies, such numerous household members depending on one social grant and transactional sex, were too often relied upon, and although they may have helped relieve the stress of shocks momentarily, they did not provide for the long-term well-being of individuals and households. Poor communication and capacity between the different levels of government and between the government (especially at the local level) and the two rural communities has created an environment full of uncertainty and lacking in advocacy. Local government needs increased human, informational, and financial capacity and a clear delegation of responsibilities amongst the different departments in order for the two communities to benefit from the implementation of support strategies. There is also a great need for educational programmes and capacity development within the two rural communities, particularly based on improved coping and longer-term adaptation strategies in response to climate change in order for households to better prepare themselves for the future.