Changes in groundwater storage in California's Central Valley (CV) are considered partly responsible for vertical uplift surrounding the southern CV and for stress changes on nearby faults. Questions remain regarding the distribution of stress on the central San Andreas fault (CSAF) from recent and historical drawdown of the CV aquifer over the past 150 years (1860–2010). We combine groundwater storage change estimates for the 2006–2010 drought with a three-dimensional finite element model to estimate Coulomb failure stress change (ΔCFS) on the CSAF. We combine a simple parameterization of historical hydraulic head change for 1860–1960 with a CV hydrological model (1961–2003) to estimate visco-elastic effects on ΔCFS total and 2010 rate. We find that ΔCFS on the CSAF correlates positively with shallow seismicity and low frequency earthquakes for both short-term and long term stressing. Unloading uplift rates surrounding the southern CV only partially account for the observed vertical GPS rates. Plain Language Summary We investigate the spatial and temporal effects of groundwater removal in California's Central Valley on ground surface deformation and on stress changes on the nearby central San Andreas fault (CSAF). In particular, we focus on two outstanding questions: (a) What are the spatial distributions of Coulomb failure stress (ΔCFS) on the CSAF? (b) What are the effects of viscoelasticity on uplift and ΔCSF over time? We focus on the well studied 2006–2010 drought, estimating the change in groundwater storage and the resulting uplift and stress change through a numerical model for the Earth. Viscoelastic effects are examined through an estimate of historical groundwater change from 1860-1961 and a hydrological model from 1961-2003 added to the 2006–2010 drought estimates. Here we find that lower crust or upper mantle viscosity variations enhance uplift and stress changes and that CSAF stress changes may accumulate with time, especially with droughts and groundwater consumption.