In 2011, exceptionally low atmospheric moisture content combined with moderately high temperatures to produce a record-high vapor pressure deficit (VPD) in the southwestern United States (SW). These conditions combined with record-low cold-season precipitation to cause widespread drought and extreme wildfires. Although interannual VPD variability is generally dominated by temperature, high VPD in 2011 was also driven by a lack of atmospheric moisture. The May-July 2011 dewpoint in the SW was 4.5 standard deviations below the long-term mean. Lack of atmospheric moisture was promoted by already very dry soils and amplified by a strong ocean-to-continent sea level pressure gradient and upper-level convergence that drove dry northerly winds and subsidence upwind of and over the SW. Subsidence drove divergence of rapid and dry surface winds over the SW, suppressing southerly moisture imports and removing moisture from already dry soils. Model projections developed for the fifth phase of the Coupled Model Intercomparison Project (CMIP5) suggest that by the 2050s warming trends will cause mean warm-season VPD to be comparable to the record-high VPD observed in 2011. CMIP5 projections also suggest increased interannual variability of VPD, independent of trends in background mean levels, as a result of increased variability of dewpoint, temperature, vapor pressure, and saturation vapor pressure. Increased variability in VPD translates to increased probability of 2011-type VPD anomalies, which would be superimposed on ever-greater background VPD levels. Although temperature will continue to be the primary driver of interannual VPD variability, 2011 served as an important reminder that atmospheric moisture content can also drive impactful VPD anomalies.