Mercury (Hg) is a global pollutant and poses a worldwide concern due to its high toxicity. Guizhou province is recognized as a heavily Hg-polluted area in China due to both the special geochemical background and human activities. Here an integrated overview of current knowledge on the behavior of Hg in environments, as well as human health risk with respect to Hg contaminations in Guizhou was presented. Two key anthropogenic Hg emission sources in Guizhou were coal combustion and metals smelting, which dominantly contributed to the high levels of Hg in local ecosystems and high fluxes of Hg deposition. The annual Hg emission from anthropogenic sources ranged between 22.6 and 55.5 t, which was about 6.3-10.3% of current total Hg emissions in China. Meanwhile, Hg Hg-enriched soil in the province serves an important natural Hg emission source to the ambient air. The local environment of Hg mining and zinc smelting areas are seriously contaminated with Hg. It is demonstrated that rice growing in Hg Hg-contaminated soil can accumulate methylmercury (MeHg) to a level to pose health threat to local inhabitants whose staple food is rice. Local inhabitants in Hg mining areas are exposed to Hg through inhalation of Hg vapor and consumption of rice with high level of MeHg. Rice intake is indeed the main MeHg exposure pathway to local inhabitants in Hg mining areas in Guizhou, which is contrary to the general point of view that fish and fish products are the main pathway of MeHg exposure to humans.