Important parameters of estuarine variability include morphology, flushing times, nutrient loading rates, and wetland: water ratios. This variability both reflects and disguises underlying relationships between the physics and biology of estuaries, which this comparative analysis seeks to reveal, using the Gulf of Mexico (GOM) estuaries as a starting point. A question used to focus this analysis is: are the GOM estuaries unique? The GOM receives the Mississippi River, a uniquely large, world-class river, which dominates the freshwater and nutrient inflows to the GOM continental shelf, whose margins include 35 major estuarine systems. These GOM estuaries have 28% and 41% of the U.S. estuarine wetlands and open water, respectively. Within the GOM, estuarine nitrogen, phosphorus, and suspended matter loading varies over 2 orders of magnitude. Anoxic estuarine events tend to occur in estuaries with relatively slow freshwater turnover and high nitrogen loading. Compared to estuaries from other regions in the U.S., the average GOM estuary is distinguished by shallower depths, faster freshwater flushing time, a higher wetland area:open water area ratio, greater fisheries yield per area wetland, lower tidal range, and higher sediment accumulation rates. The average GOM estuary often, but not always, has a flora and fauna not usually found in most other U.S. estuaries (e.g., manatees and mangroves). Coastal wetland loss in the GOM is extraordinarily high compared to other regions and is causally linked to cultural influences. Variations in nutrient loading and population density are very large among and within estuarine regions. This variation is large enough to demonstrate that there are insufficient systematic differences among these estuarine regions that precludes cross-system analyses. There are no abrupt discontinuities among regions in the fisheries yields per wetland area, tidal amplitude and vegetation range, salt marsh vertical accretion rates and organic accumulations, nitrogen retention, or wetland restoration rates. These results suggest that a comparative analysis emphasizing forcing functions, rather than geographic uniqueness, will lead to significant progress in understanding how all estuaries function, are perturbed, and even how they can be restored.