In the 1970s, the discovery of much higher mercury (Hg) concentrations in Mediterranean fish than in related species of the same size from the Atlantic Ocean raised serious concerns about the possible health effects of neurotoxic monomethylmercury (MMHg) on end consumers. After 50 years, the cycling and fluxes of the different chemical forms of the metal between air, land, and marine environments are still not well defined. However, current knowledge indicates that the anomalous Hg accumulation in Mediterranean organisms is mainly due to the re-mineralization of organic material, which favors the activity of methylating microorganisms and increases MMHg concentrations in low-oxygen waters. The compound is efficiently bio-concentrated by very small phytoplankton cells, which develop in Mediterranean oligotrophic and phosphorous-limited waters and are then transferred to grazing zooplankton. The enhanced bioavailability of MMHg together with the slow growth of organisms and more complex and longer Mediterranean food webs could be responsible for its anomalous accumulation in tuna and other long-lived predatory species. The Mediterranean Sea is a “hotspot” of climate change and has a rich biodiversity, and the increasing temperature, salinity, acidification, and stratification of seawater will likely reduce primary production and change the composition of plankton communities. These changes will likely affect the accumulation of MMHg at lower trophic levels and the biomagnification of its concentrations along the food web; however, changes are difficult to predict. The increased evasion of gaseous elemental mercury (Hg°) from warming surface waters and lower primary productivity could decrease the Hg availability for biotic (and possibly abiotic) methylation processes, but lower oxygen concentrations in deep waters, more complex food webs, and the reduced growth of top predators could increase their MMHg content. Despite uncertainties, in Mediterranean regions historically affected by Hg inputs from anthropogenic and geogenic sources, such as those in the northwestern Mediterranean and the northern Adriatic Sea, rising seawater levels, river flooding, and storms will likely favor the mobilization of Hg and organic matter and will likely maintain high Hg bioaccumulation rates for a long time. Long-term studies will, therefore, be necessary to evaluate the impact of climate change on continental Hg inputs in the Mediterranean basin, on air–sea exchanges, on possible changes in the composition of biotic communities, and on MMHg formation and its biomagnification along food webs. In this context, to safeguard the health of heavy consumers of local seafood, it appears necessary to develop information campaigns, promote initiatives for the consumption of marine organisms at lower trophic levels, and organize large-scale surveys of Hg accumulation in the hair or urine of the most exposed population groups.