Through a series of groundwater flow and ⁴He transport simulations, this study illustrates the conceptual and practical gains achieved by expanding a two-dimensional (2-D) model to a true 3-D one through an application in the Carrizo aquifer and surrounding formations in southwestern Texas. The 3-D simulations allow for a more detailed and accurate definition of the heterogeneities of the system by specifically identifying and differentiating processes that directly impact the three-dimensional hydraulic conductivity field. It is shown that while hydraulic conductivity decreases exponentially along the regional groundwater flow direction, such decrease is better described as a function of depth rather than recharge distance. This relationship reflects the combined influences of differential compaction of the media as well as downdip lithological change. The intrinsic permeability derived from this relationship agrees with field information and with previous findings obtained for the continental crust for depths ≤2 km, suggesting that for large scales, decrease rate of permeability with depth is independent of the media. Results also suggest that the solution for groundwater flow simulations based on calibration of hydraulic heads depends on the ratio between hydraulic conductivities of different formations, indicating that an infinite number of solutions are available for calibration of 3-D groundwater flow models. Understanding how geological processes directly affect the 3-D hydraulic conductivity field at the regional scale is essential not only to hydrogeological applications but also at improving our understanding of the Earth's crust and mantle dynamics by allowing for a more accurate quantification of helium and heat fluxes.