If habitat destruction or overexploitation of populations is severe, species loss can occur directly and abruptly. Yet the final descent to extinction is often driven by synergistic processes (amplifying feedbacks) that can be disconnected from the original cause of decline. We review recent observational, experimental and meta-analytic work which together show that owing to interacting and self-reinforcing processes, estimates of extinction risk for most species are more severe than previously recognised. As such, conservation actions which only target single-threat drivers risk being inadequate because of the cascading effects caused by unmanaged synergies. Future work should focus on how climate change will interact with and accelerate ongoing threats to biodiversity, such as habitat degradation, overexploitation and invasive species.