A regional flow and transport model is used to explore the implications of significant variability in Pleistocene and Holocene climates on hydraulic heads and 14C activity. Simulations involve a 39 km slice of the Death Valley Flow System through Yucca Mountain toward the Amargosa Desert. The long-time scale over which infiltration has changed (tens-of-thousands of years) is matched by the large physical extent of the flow system (many tens-of-kilometers). Estimated paleo-infiltration rates were estimated using a juniper pollen percentage that extends from the last interglacial (LIG) period (approximately 120 kyrbp) to present. Flow and 14C transport simulations show that groundwater flow changes markedly as a function of paleoclimate. At the last glacial maximum (LGM, 21 kyrbp), the recharge to the flow system was about an order-of-magnitude higher than present, and water table was more than 100 m higher. With large basin time constants, flow is complicated because hydraulic heads at a given location reflect conditions of the past, but at another location the flow may reflect present conditions. This complexity is also manifested by processes that depend on flow, for example 14C transport. Without a model that accounts for the historical transients in recharge for at least the last 20,000 years, there is no simple way to deconvolve the 14C dates to explain patterns of flow.