Anthropogenic and natural disturbances to freshwater quantity and quality is a greater issue for society than ever before. To successfully restore water resources in impaired watersheds requires understanding the interactions between hydrology, climate, land use, water quality, ecology, social and economic pressures. Current understanding of these interactions is limited primarily by a lack of innovation, investment, and interdisciplinary collaboration. This Special Issue of Water includes 18 articles broadly addressing investigative areas related to experimental study designs and modeling (n = 8), freshwater pollutants of concern (n = 7), and human dimensions of water use and management (n = 3). Results demonstrate the immense, globally transferable value of the experimental watershed approach, the relevance and critical importance of current integrated studies of pollutants of concern, and the imperative to include human sociological and economic processes in water resources investigations. Study results encourage cooperation, trust and innovation, between watershed stakeholders to reach common goals to improve and sustain the resource. The publications in this Special Issue are substantial; however, managers remain insufficiently informed to make best water resource decisions amidst combined influences of land use change, rapid ongoing human population growth, and changing environmental conditions. There is thus, a persistent need for further advancements in integrated and interdisciplinary research to improve scientific understanding, management and future sustainability of water resources.