Ecological and paleoecological studies from the Patuxent River mouth reveal dynamic variations in benthic ostracode assemblages over the past 600 years due to climatic and anthropogenic factors. Prior to the late 20th century, centennial-scale changes in species dominance were influenced by climatic and hydrological factors that primarily affected salinity and at times led to oxygen depletion. Decadal-scale droughts also occurred resulting in higher salinities and migration of ostracode species from the deep channel (Loxoconcha sp., Cytheromorpha newportensis) into shallower water along the flanks of the bay. During the 19th century the abundance of Leptocythere nikraveshae and Perissocytheridea brachyforma suggest increased turbidity and decreased salinity. Unprecedented changes in benthic ostracodes at the Patuxent mouth and in the deep channel of the bay occurred after the 1960s when Cytheromorpha curta became the dominant species, reflecting seasonal anoxia. The change in benthic assemblages coincided with the appearance of deformities in foraminifers. A combination of increased nitrate loading due to greater fertilizer use and increased freshwater flow explains this shift. A review of the geochemical and paleoecological evidence for dissolved oxygen indicates that seasonal oxygen depletion in the main channel of Chesapeake Bay varies over centennial and decadal timescales. Prior to 1700 AD, a relatively wet climate and high freshwater runoff led to oxygen depletion but rarely anoxia. Between 1700 and 1900, progressive eutrophication occurred related to land dearance and increased sedimentation, but this was superimposed on the oscillatory pattern of oxygen depletion most likely driven by climatological and hydrological factors. It also seems probable that the four- to five-fold increase in sedimentation due to agricultural and timber activity could have contributed to an increased natural nutrient load, likely fueling the early periods (1700-1900) of hypoxla prior to widespread fertilizer use. Twentieth-century anoxia worsened in the late 1930s-1940s and again around 1970, reaching unprecedented levels in the past few decades. Decadal and interannual variability in oxygen depletion even in the 20th century is still strongly influenced by climatic processes influencing precipitation and freshwater runoff.