Reliable quantitative information on sediment sources to rivers is critical to mitigate contamination and target conservation and restoration actions. However, the determination of the relative importance of sediment sources is complicated at the scale of large river basins by immense variability in erosional processes and sediment sources over space and time, heterogeneity in sediment transport and deposition, and a paucity of sediment monitoring data. Sediment source fingerprinting is an increasingly adopted field-based technique that identifies the nature and relative source contribution of sediment transported in waterways. Notably, sediment source fingerprinting provides information that is independent of other field, modeling, or remotely sensed techniques. However, the diversity in sediment fingerprinting sampling, analytical, and interpretive methods has been recognized as a problem in terms of developing standardized procedures for its application at the scale of large river basins. Accordingly, this review focuses on established sediment source fingerprinting studies conducted within the Mississippi River Basin (MRB), summarizes unique information provided by sediment source fingerprinting that is distinct from traditional monitoring techniques, evaluates consistency and reliability of methodological approaches among MRB studies, and provides prospects for the use of the sediment source fingerprinting technique as an aid to large-scale landscape conservation and restoration under current management frameworks. Most established MRB studies got creditable fingerprinting results and considered near-channel sources as the dominant sediment sources in most cases, while the comparability of their results suffers from a lack of standardization in procedural steps. Findings from MRB studies demonstrate that sediment source fingerprinting is a highly valuable and reliable sediment source assessment approach to assist land and water resource management under current management frameworks, but efforts are still needed to make this technique ready to be used in a more predominant way in large-scale landscape conservation and restoration efforts. We summarized research needs and suggested the best fingerprinting practices for management purposes with the aim of ensuring that this technique is as robust and reliable as it moves forward.