The Minamata Convention to reduce anthropogenic mercury (Hg) emissions entered into force in 2017, and attention is now focused on how to best monitor its effectiveness at reducing Hg exposure to humans. A key question is how closely Hg concentrations in the human food chain, especially in fish and other aquatic wildlife, will track the changes in atmospheric Hg that are expected to occur following anthropogenic emission reductions. We investigated this question by evaluating several regional groups of case studies where Hg concentrations in aquatic biota have been monitored continuously or intermittently for several decades. Our analysis shows that in most cases Hg time trends in biota did not agree with concurrent Hg trends in atmospheric deposition or concentrations, and the divergence between the two trends has become more apparent over the past two decades. An over-arching general explanation for these results is that the impact of changing atmospheric inputs on biotic Hg is masked by two factors: 1) The aquatic environment contains a large inventory of legacy emitted Hg that remains available for bio-uptake leading to a substantial lag in biotic response time to a change in external inputs; and 2) Biotic Hg trends reflect the dominant effects of changes in multi-causal, local and regional processes (e.g., aquatic or terrestrial biogeochemical processes, feeding ecology, climate) that control the speciation, bioavailability, and bio-uptake of both present-day and legacy emitted Hg. Globally, climate change has become the most prevalent contributor to the divergence. A wide range of biotic Hg outcomes can thus be expected as anthropogenic atmospheric Hg emissions decline, depending on how these processes operate on specific regions and specific organisms. Therefore, evaluating the effectiveness of the Minamata Convention will require biomonitoring of multiple species that represent different trophic and ecological niches in multiple regions of the world.