Abstract: BCS Ⅱ drugs are characterized by low solubility and high permeability. Improving their solubility is considered an important approach to improve its oral absorption. Recent strategies to increase the solubility of poorly-soluble drugs may unexpectedly result in greatly depressed permeability, ultimately leading to failure in improving oral absorption. Based on the mathematics of membrane permeability coefficient of a drug, the membrane/aqueous partition coefficient is dependent on the drug's solubility in the gastrointestinal milieu, suggesting a unique interplay between the solubility and permeability of the drug, and treating the one irrespectively of the other may be insufficient. When we focus on the increase of drug solubility and overlook the efficacy of drug permeability, the positive effect of increased solubility to drug oral absorption might be traded off by depressed permeability. To provide rational formulary designs, by optimizing excipients and evaluation, this review summarizes solubility-permeability interplay for different types of solubilizing techniques, such as cyclodextrin, surfactants-based vehicle, cosolvent, amorphous solid dispersions, other infectors such as P-gp transporters and new techniques for simultaneous evaluation of drug solubility and permeability.