The reference condition paradigm has served as the standard for assessing the outcomes of restoration projects, particularly their success in meeting project objectives. One limitation of relying solely on the reference condition in designing and monitoring restoration projects is that reference conditions do not necessarily elucidate impairments to effective restoration, especially diagnosing the causal mechanisms behind unsuccessful outcomes. We provide a spatial framework to select both reference and non-reference streams to guide restoration planning and long-term monitoring through reliance on anthropogenically altered ecosystems to understand processes that govern ecosystem biophysical properties and ecosystem responses to restoration practices. We then applied the spatial framework to East Fork Poplar Creek (EFPC), Tennessee (USA), a system receiving 30 years of remediation and pollution abatement actions from industrialization, pollution, and urbanization. Out of > 13,000 stream reaches, we identified anywhere from 4 to 48 reaches, depending on the scenario, that could be used in restoration planning and monitoring for specific sites. Preliminary comparison of fish species composition at these sites compared to EFPC sites were used to identify potential mechanisms limiting the ecological recovery following remediation. We suggest that understanding the relative role of anthropogenic pressures in governing ecosystem responses is required to successful, process-driven restoration.