Water isotopes provide a clear record of past climate variability but establishing their precise relationship to local or regional climate changes is the key to quantitative interpretations. We have incorporated water isotope tracers within the complete hydrological cycle of Goddard Institute for Space Studies coupled ocean-atmosphere model (ModelE) in order to assess these relationships. Using multicentennial simulations of the modern (preindustrial) and mid-Holocene (6 kyr BP) climate, we examine the internal variability and the forced response to orbital and greenhouse gas forcing. Modelled isotopic anomalies clearly reflect climatic changes and, particularly in the tropics, are more regionally coherent than the precipitation anomalies. Matches to observations at the mid-Holocene and over the instrumental period are good. We calculate water isotope-climate relationships for many patterns of intrinsic and for forced variability relevant to the Holocene, and we show that in general, calibrations depend on the nature of the climate change. Specifically, we examine relationships between isotopes in precipitation and local temperatures and precipitation amounts in the principal ice coring regions (Greenland, Antarctica, and the tropical Andes) and the seawater isotope-salinity gradients in the ocean. We suggest that isotope-based climate reconstructions based on spatial patterns and nonlocal calibrations will be more robust than interpretations based on local relationships.