Half a century of mercury research has provided scientists and policy makers with a detailed understanding of mercury toxicology, biogeochemical cycling and past and future impacts on human exposure. The complexity of the global biogeochemical mercury cycle has led to repeated and ongoing paradigm shifts in numerous mercury-related disciplines and outstanding questions remain. In this review, we highlight some of the paradigm shifts and questions on mercury toxicity, the risks and benefits of seafood consumption, the source of mercury in seafood, and the Arctic mercury cycle. We see a continued need for research on mercury toxicology and epidemiology, for marine mercury dynamics and ecology, and for a closer collaboration between observational mercury science and mercury modeling in general. As anthropogenic mercury emissions are closely tied to the energy cycle (in particular coal combustion), mercury exposure to humans and wildlife are likely to persist unless drastic emission reductions are put in place.