Methylmercury (MeHg) is a causative agent of Minamata disease and an environmental pollutant that comprises a large portion of organically occurring mercury. Many aspects of the biological defense mechanisms against MeHg toxicity remain unclear. Recently, nuclear factor-E2-related factor 2 (Nrf2), heat shock factor protein 1 (Hsf1), and hydrogen sulfide were identified as intracellular defense factors against MeHg toxicity. These findings suggest that novel biological defense mechanisms against MeHg toxicity exist in the living organism. In addition, the expression of downstream genes that mediate activation of the transcription factors Nrf2 and Hsf1 was markedly induced by MeHg treatment, suggesting that this action is involved in the reduction of MeHg toxicity. On the other hand, when the gaseous form of hydrogen sulfide (H(2)S) binds directly to MeHg, bismethylmercury sulfide (MeHg-S-HgMe) as a low toxicity metabolite is formed. This suggests the involvement of the gaseous form of H(2)S in the reduction of MeHg toxicity. In this topic, we summarize the roles of factors involved in novel biological defense mechanisms against MeHg toxicity.