In this study, I use bioarchaeological data derived from human burials to evaluate subsistence change in mid-to-late Holocene central California (circa 4950-200 B.P.). Previous investigations in the region have proposed two competing models to account for changes in subsistence patterns. The seasonal stress hypothesis argues that the increased reliance on acorns and small seeds during the late Holocene led to improved health status, since these resources could be stored and used as a “buffer” against seasonal food shortages. In contrast, resource intensification models predict temporal declines in health during the late Holocene, as measured by a decline in dietary quality and health status, increased population crowding, and greater levels of sedentism. I test the hypothesis that health status, as measured by childhood stress and disease indicators, declined during the late Holocene in central California. I analyzed 511 human skeletons from ten archaeological sites in the Sacramento Valley and San Francisco Bay area to investigate temporal and spatial variability in diet and health. I analyzed a subset (n = 111) of this sample to evaluate prehistoric dietary patterns using carbon and nitrogen stable isotope ratios. Indicators of health status show significant temporal and regional variation. In the Valley, tibial periosteal reactions, porotic hyperostosis, and enamel hypoplasias significantly increased through time, implying a decline in health status. In the Bay, health indicators show little temporal variability. However, inter-regional comparisons indicate a higher prevalence of stress and disease indicators among Bay Area skeletons than in the Valley skeletal series. The stable isotope data from human bone collagen and apatite also indicate significant interregional differences in prehistoric diets between the Bay and the Valley. In the Bay, diets shifted from high trophic level marine foods to a more terrestrially focused diet over time. In the Valley, there are no significant dietary trends observed in the data. Dental caries and antemortem tooth loss are significantly more prevalent in the Valley than in the Bay, and closely match the isotopic findings. The paleopathological findings provide support for late Holocene resource intensification models posited for the Valley, but not for the Bay Area.