The Lez aquifer in southern France comprises low-porosity karstified limestones and provides drinking water for ~400,000 inhabitants. Population growth and climate change have increased the stress on the water resources. In order to provide long-term protection and to optimize the water supply, the hydrogeology of the Lez aquifer must be better characterized. This study focused particularly on the St-Clément major fault zone (12 km long with a 500-m normal throw) which was structurally characterized using accurate geological mapping of the area, outcrops analysis and geophysics tools. The research highlights and explains the close relationship between the fault and the karstic occurrences. Moreover, tracer tests and piezometric head variations in boreholes have shown (1) strong interconnection between the observed karstic formations and (2) the major role of St-Clément fault on mass and pressure transfers in the aquifer. At the reservoir scale, the other major faults of the Lez aquifer, such as Corconne-Matelles or Gourg Noir faults, have shown some common morphologic and dynamic characteristics, and suggest a similar hydrogeological functioning. This study then extends this model to a larger scale. It proposes that, in aquifers of low-porosity carbonates, fault zones control the development of the main karstic network which, in turn, controls the main groundwater flows. Thus, faults should be reconsidered in order to improve the vulnerability studies and the quality of karstic aquifer modelling. Therefore, this report can contribute to protecting the groundwater resource, improving yields and optimizing groundwater supply exploitation in this type of aquifer.