Processes of fluid flow and chemical transport through the vadose zone can be characterized through the isotopic systematics of natural soils, minerals, pore fluids, and groundwater. In this contribution, we first review our research using measured isotopic variations, due both to natural and site-related processes, of the elements H, O, N, Sr, and U, to study the interconnection between vadose zone and groundwater contamination at the Hanford Site in south-central Washington State. We follow this brief review with a presentation of new data pertaining to vadose zone and groundwater contamination in the Waste Management Area (WMA) T-TX-TY vicinity. Uranium isotopic data for the C3832 core (WMA TX) indicate the involvement of processed natural U fuel and link the observed U contamination to releases near single-shelled tank TX-104. The data also preclude contamination from an early 1970s TX-107 leak. In the case of the C4104 core (WMA T), the U isotopic data indicate a mixture of processed natural and enriched U fuels consistent with the major leak from T-106 in 1973. Uranium and strontium isotopic data for the cores also provide direct evidence for chemical interaction between high-pH waste fluid and sediment. Isotopic data (δ15N and δ18O) for groundwater nitrate contamination in multidepth samples just to the northeast of WMA T are distinct from that seen in surrounding wells and suggest tank waste (possibly from the 1973 T-106 event) as a source of very high 99Tc concentrations recently observed at the northeast corner of WMA T.