The Colorado River is the primary surface water resource in the rapidly growing U.S. Southwest. Over the period 1916-2014, the Upper Colorado River Basin naturalized streamflow declined by 16.5%, despite the fact that annual precipitation in the UCRB over that period increased slightly (+1.4%). In order to examine the causes of the runoff declines, we performed a set of experiments with the Variable Infiltration Capacity hydrology model. Our results show that the pervasive warming has reduced snowpacks and enhanced evapotranspiration over the last 100years; over half (53%) of the long-term decreasing runoff trend is associated with the general warming. Negative winter precipitation trends have occurred in the handful of highly productive subbasins that account for over half of the streamflow at Lee's Ferry. We also compared a midcentury drought with the (ongoing) post-Millennium Drought and find that whereas the earlier drought was caused primarily by pervasive low-precipitation anomalies across UCRB, higher temperatures have played a large role in the post-Millennium Drought. The post-Millennium Drought has also been exacerbated by negative precipitation anomalies in several of the most productive headwater basins. Finally, we evaluate the UCRB April-July runoff forecast for 2017, which decreased dramatically as the runoff season progressed. We find that while late winter and spring 2017 was anomalously warm, the proximate cause of most of the forecast reduction was anomalous late winter and early spring dryness in UCRB, which followed exceptionally large (positive) early winter precipitation anomalies. Plain Language Summary As the essential water resource for the Southwest United States, the Upper Colorado River Basin (UCRB) unimpaired streamflow declined by 16.5% over 1916-2014, while annual precipitation increased slightly (+1.4%). We performed a set of experiments with a hydrology model that uses temperature and precipitation as inputs to diagnose the causes of this apparent anomaly. We find that over half (53%) of the decreasing runoff trend is associated with unprecedented basin-wide warming, which has reduced snowpack and increased plant water use. The remaining similar to 47% of the trend is associated mostly with reduced winter precipitation in four highly productive subbasins, all located in Colorado. We compared the 1953-1967 drought with the 2000-2014 Millennium Drought and find that the earlier drought was caused primarily by precipitation declines across the entire UCRB but higher temperatures caused about half of the 2000-2014 flow loss. The Millennium Drought was also caused by precipitation reductions in the four most productive subbasins. We evaluated the UCRB April-July runoff forecast for 2017, which decreased dramatically as the runoff season progressed. The late winter and spring 2017 was anomalously warm, but most of the reduction was due to late season dryness.