Experimental evidence shows that changes in pore water chemistry can significantly affect the mechanical behavior of saturated active clays. Despite this evidence, how the chemical composition of the pore water can be considered in effective stress definition is questionable. This paper develops the concept of generalized effective stress for active clays. To this end, physicochemical studies on water–clay mineral interactions are used to clearly define the different types of ions and water present in an active clay. In particular, the presence of both movable and non-movable ions within the liquid water is highlighted. Taking this into account, thermodynamic and geochemistry principles are applied to the representative elementary volume scale for determining the pore water pressure and redefine the effective stress accordingly. The theoretical development results in the dependence of the effective stress on the pore water chemistry through the effective solute suction variable. Equations for the determination of this chemical variable are developed. The implications of the use of the proposed effective stress concept are investigated using experimental results taken from the literature. The results show advantages both in the interpretation of shear strength and volumetric data, and all support the theoretical explanation underlying the proposed concept.