Most human exposure to mercury (Hg) in the United States is from consuming marine fish and shellfish. The Gulf of Maine is a complex marine ecosystem comprising twelve physioregions, including the Bay of Fundy, coastal shelf areas and deeper basins that contain highly productive fishing grounds. Here we review available data on spatial and temporal Hg trends to better understand the drivers of human and biological exposures. Atmospheric Hg deposition from U.S. and Canadian sources has declined since the mid-1990s in concert with emissions reductions and deposition from global sources has increased. Oceanographic circulation is the dominant source of total Hg inputs to the entire Gulf of Maine region (59%), followed by atmospheric deposition (28%), wastewater/industrial sources (8%) and rivers (5%). Resuspension of sediments increases MeHg inputs to overlying waters, raising concerns about benthic trawling activities in shelf regions. In the near coastal areas, elevated sediment and mussel Hg levels are co-located in urban embayments and near large historical point sources. Temporal patterns in sentinel species (mussels and birds) have in some cases declined in response to localized point source mercury reductions but overall Hg trends do not show consistent declines. For example, levels of Hg have either declined or remained stable in eggs from four seabird species collected in the Bay of Fundy since 1972. Quantitatively linking Hg exposures from fish harvested from the Gulf of Maine to human health risks is challenging at this time because no data are available on the geographic origin of seafood consumed by coastal residents. In addition, there is virtually no information on Hg levels in commercial species for offshore regions of the Gulf of Maine where some of the most productive fisheries are located. Both of these data gaps should be priorities for future research.