Changes in groundwater quality have been evaluated for more than 2,200 wells in 25 Principal Aquifers in the United States based on repeated decadal sampling (once every 10 years) from 1988 to 2021. The purpose of this study is to identify contaminants with changing concentrations, the locations and magnitude of those changes, the factors driving those changes, the obstacles to interpreting the changes, and approaches to ameliorate those obstacles. Sampling was conducted in 89 networks of 20–30 wells each that represent various geographic regions, aquifer types and land use types. Each network, and the wells that comprise them, are sampled on a rotating basis once every 10 years. Of the 28 constituents evaluated for trends, concentrations of Na, Cl, dissolved solids, SO4, and NO3 exhibited statistically significant increases at the network level more frequently than other constituents. Factors affecting trends in Cl and NO3 are emphasized in this study. Regional patterns show large increases of Cl in urban areas in the Northeast and Midcontinent, where road-deicing salt application rates are 10 to 100 times greater than in other regions of the country, and in semiarid and arid regions of the western United States, where evaporation concentrates solutes in recharge. The largest increases in NO3 were in agricultural areas of the semiarid west, arid west and Pacific regions which are characterized by oxic groundwater, long-term increases in nitrogen fertilizer usage, and high rates of irrigation. However, finding a direct relation between increasing contaminant sources and corresponding groundwater quality response, particularly when sampling once every 10 years, can be complicated by factors such as uncertainty in the timing, mass, and location of contaminant sources, groundwater residence time (recharge date), geochemical conditions in the aquifer that affect contaminant transport, and variability in water quality due to climatic factors such as seasonality and hydrologic conditions. Understanding groundwater residence time allows the changes in groundwater quality to be evaluated in the context of recharge date rather than the sample date. Likewise, information on geochemical characteristics of the aquifer can be helpful for understanding relations between contaminant source inputs and groundwater concentrations. For example, oxic geochemical conditions in the aquifer may allow for conservative transport and accumulation of NO3 in groundwater, whereas reducing environments could favor NO3 degradation. Differences in hydrologic conditions (wetter or drier than average) on the date of sampling could impact the statistical results of sampling at decadal intervals and obscure long-term patterns. Samples collected under substantially different hydrologic conditions can be identified, and high-frequency sampling can improve interpretation of measured results in these cases. Although decadal sampling and associated water-quality interpretations have limitations, repeated, scheduled sampling of thousands of wells over multiple decades has great value for identifying and understanding long-term, regional groundwater-quality trends. Despite these limitations, the concepts presented herein provide options that could be used to interpret trends or changes when sampling over longer timespans, which is less common than trend networks with higher frequency sampling intervals.