The effectiveness of ecological restoration efforts on large developed rivers is often unknown because comprehensive ecological monitoring programs are often absent. Although Eulerian water-quality monitoring programs, such as the National Stream Quality Accounting Network (NASQAN) program, are more common, they are usually not designed for ecological assessment. Therefore, this paper addresses the value of NASQAN for ecological assessments on the Missouri River and identifies potential program additions and modifications to assess certain ecological changes in physical habitat, biological structure and function, and ecotoxicity. Five additional sites: The analysis of chlorophyll, mercury, ATP, potential endocrine disruptors, total trace elements, and selected total hydrophobic organics; and the hourly measurement of dissolved oxygen, turbidity, and temperature are recommended. Hourly measurements would require an entirely new operational aspect to NASQAN. However, the presence of data loggers and satellite transmitters in the gauging stations at all NASQAN sites substantially improves the feasibility of continuous water-quality monitoring. The use of semipermeable membrane devices (SPMDs) to monitor dissolved bioaccumulating organics and trace elements, identification and enumeration of zooplankton, and characterization of the bioavailability of organic matter are also recommended. The effect of biological processes on the conservative assumptions that are used in flux and source determinations of NASQAN constituents are also evaluated. Organic carbon, organic nitrogen, dissolved phosphate, and dissolved inorganic nitrogen are the NASQAN constituents most vulnerable to biological processes and thus violation of conservative assumptions.