ABSTRACT The distribution of eastern oysters Crassostrea virginica near terrestrial watersheds has led to a general impression that low or variable salinity is imperative for survival. However, freshwater runoff contains numerous mineral elements from geologic deposits that could play significant roles in oyster physiology. Two metals of terrestrial origin, copper and zinc, are accumulated to extremely high concentrations in eastern oysters, even in the absence of anthropogenic sources. As yet, there has been no defendable demonstration of a physiologic function for such high concentrations. Both copper and zinc, however, are accumulated almost exclusively in the amebocytes and calcareous shell of oysters, a unique distribution that implicates a role in the functions of amebocytes. Amebocytes are migratory, diapedetic cells generally recognized to provide nutriment and defense through phagocytosis, killing, and digestion of invading or ingested microorganisms. There is sufficient evidence in existing literature to suggest that copper and zinc directly contribute to these antimicrobial activities. This review presents historical and recent findings that demonstrate a strong affinity of oyster amebocytes for copper and zinc (even in low ambient concentrations), prolonged retention of the metals despite a potential route of elimination, and strong circumstantial evidence of antimicrobial activity by accumulated copper and zinc. It is proposed that oysters actively concentrate copper and zinc as antimicrobial agents to be used in intracellolar and extracellular killing (direct toxicity) as well as extracellular clot formation (precipitation of hemolymph). This potential, combined with evidence of amebocyte involvement in deposition of oyster shell, provides an alternative framework for understanding amebocyte functions, defense activities, and coastal distributions of oyster populations. It also affords some resolution to the apparent contradiction of eastern oysters thriving at seemingly polluted locations.