Rapid global environmental change combined with other stressors is increasing the vulnerability of poor people worldwide. In South Africa, HIV/AIDS and climate variability, interacting with other localised risks are having differential impacts across communities, households and individuals. These stressors have the effect of undermining livelihood assets, decreasing adaptive capacity and constraining the ability to respond to new threats such as those expected under a changing climate. This Article considers the gendered implications of multiple stressors on livelihoods drawing on empirical data from a four-year research project in two sites in the Eastern Cape, South Africa. The research was broadly framed within a livelihoods-entitlements approach and methods included a household survey, interviews and focus group discussions. Using data from these sources, this Article explores gender-differentiated vulnerability through an analysis of household livelihoods and assets, perceptions of vulnerability and food security, and the types of responses employed when faced with shocks and stress. Our findings indicate that although women and female-headed households are generally poorer and more at risk than men and male-headed households, in some situations women may be more innovative in their individual and collective responses to stressors and may have more social capital to draw on. Furthermore, men and male-headed households also face specific gender related vulnerabilities. We comment on the need to understand the underlying causes of vulnerability and the heterogeneity that exists at the local level, and consider how such knowledge can be translated into approaches that address vulnerability now and in the future.