The Mississippi Sound and the adjoining bay systems such as Mobile Bay, Biloxi Back Bay and Bay St. Louis in the Northern Gulf of Mexico are important areas of interest in the continental United States from many perspectives, such as commercial, military and recreational. The present study, called the Northern Gulf of Mexico Littoral Initiative (NGLI), is designed to assist local, state and federal agencies plan for resource management and military training in the Mississippi Sound/Bight. A regional scale modeling system focusing on the Mississippi sound and the adjoining bay systems has been developed to provide a reliable means to predict the littoral circulation and salinity structure in the region. The modeling framework adopts a high-resolution orthogonal curvilinear grid, which greatly resolves the bathymetric and coastline features of the region, especially the area in the vicinity of the barrier islands and ship channels. Spatially variable wind and pressure fields generated from the Coupled Ocean/Atmospheric Prediction System (COAMPS) have been integrated in the modeling system. The model has been calibrated against water level data for the January–April 2000 period at Biloxi and Bay St. Louis stations. Processes controlled by winds and freshwater discharges have been identified and analyzed. Modeling simulations have been performed to assess the impact of wind forcing and freshwater discharges on the salinity structure in the bay systems and in the Mississippi Sound. Two different flow regimes have been considered, the spring-average high flow and summer-average low flow conditions. Between these extreme freshwater discharges the systems exhibit a variety of dispersion patterns that lead to significant variations in longitudinal, lateral and vertical salinity structure. It has been demonstrated that the salinity front in the Mobile Bay, Biloxi Back Bay and Bay St. Louis is extremely sensitive to the strength of the freshwater flow and the wind conditions. During the spring high flow period, Mobile Bay, for example, may well turn in to a near limnetic system, whereas, during the summer low flow period the salinity in the upper bay may reach as high as 26 ppt.