Runoff from mountaintop mining altered watersheds in the Appalachian region (USA) is known to pollute headwater streams, yet regional scale assessments of water quality have focused on salinization and selenium. We conducted a comprehensive survey of inorganic contaminants found in 170 stream segments distributed across a spectrum of historic and contemporary human land use. Principal component (PC) analysis identified 3 important dimensions of variation in water chemistry that were significantly correlated with contemporary surface mining (PC1, elevated dominant ions, sulfate, alkalinity, and selenium), coal geology and legacy mines (PC2, elevated trace metals), and residential development (PC3, elevated sodium and chloride). The combination of these 3 dominant sources of pollutants produced a complex stream-to-stream patchwork of contaminant mixtures. Seventy-five percent of headwater streams (catchments 5km2) were classified as having reference chemistries, and chemistries indicative of combined mining and development contaminants accounted for 47% of larger streams (compared to 26% of headwater streams). Extreme degradation of larger streams can be attributed to accumulation of contaminants from multiple human land use activities that include contemporary mountaintop mining, underground mining, abandoned mines, and untreated domestic wastewater. Consequently, water quality improvements in this region will require a multi-contaminant remediation approach.