The limited aqueous solubility of active pharmaceutical ingredients (APIs) remains a major challenge in drug development, severely compromising clinical performance. Crystal engineering has emerged as a powerful and versatile approach to address this issue by rationally designing API crystal structures through precise control of intermolecular interactions, thereby enhancing solubility, dissolution rates, and ultimately bioavailability. This review systematically summarizes recent advances in crystal engineering strategies for poorly water-soluble drugs, including polymorphs, cocrystals, solvates/hydrates, nanocrystals, organic framework solids, solid solutions, liquid crystals, amorphous solids, and salts. Additionally, key challenges in translational applications are discussed, including structure-property relationship, AI-driven computational modeling, <i>in vitro</i>-<i>in vivo</i> correlation establishment, and advanced crystallization techniques. The review aims to provide strategic insights of crystal engineering for overcoming solubility barriers in next-generation drug formulations. Abstract The limited aqueous solubility of active pharmaceutical ingredients (APIs) remains a major challenge in drug development, severely compromising clinical performance. Crystal engineering has emerged as a powerful and versatile approach to address this issue by rationally designing API crystal structures through precise control of intermolecular interactions, thereby enhancing solubility, dissolution rates, and ultimately bioavailability. Active pharmaceutical ingredients (APIs) with low aqueous solubility often exhibit poor absorption and limited oral bioavailability, posing significant formulation challenges that hinder drug development and compromise clinical performance 3 , 4 . Crystal engineering was first proposed by Pepinsky in 1955, with Schmidt subsequently establishing the fundamental principles of this discipline 5 . Cocrystallization strategy has been widely used to improve the solubility, dissolution performance and thus oral bioavailability of poorly soluble drugs 116 , 117 , 118 . From a thermodynamic perspective, the incorporation of water-soluble coformers into the crystal lattice reduces the hydration barrier of hydrophobic drug cocrystals, with an extent proportional to that of the pure coformer 119 . Consequently, cocrystal solubility demonstrates a direct dependence on the coformer's solubility 119 . During the dissolution, the highly soluble coformer rapidly leaches out from the cocrystal lattice, promoting drug release and generating supersaturation of the API 120 . Figure 14 Pharmaceutical nanocrystal technology has been validated as an effective strategy for addressing the critical biopharmaceutical challenges associated with poorly water-soluble drugs. Owing to their nanoscale dimensions, nanocrystals markedly increase drug solubility and dissolution performance, thereby improving oral bioavailability 12 , 182 . Etoposide (ETO) is an antitumor drug approved for treating testicular and small cell lung cancer. However, ETO has limited oral absorption due to its poor water solubility and permeability 183 . Wang and coworkers 12 developed a nanocrystal-loaded lipid carrier, ETO (ETO-EU@Lipo@NCs), to improve its oral absorption and anticancer efficacy. MOFs have demonstrated significant potential in enhancing the phase stability, solubility, and bioavailability of poorly water-soluble drugs 214 , 215 . The incorporation of amorphous drugs into MOFs can inhibit crystallization and maintain the drugs in the amorphous state, thereby increasing their solubility. Simultaneously, MOFs optimize the dissolution of poorly water-soluble drugs by increasing the effective surface area of encapsulated drugs, analogous to particle size reduction techniques 13 , 216 , 217 . 23 ), saperconazole, methotrexate, fenoprofen, nafoxidine hydrochloride, cyclosporine) and LLCs ( e.g. , fenoprofen calcium, ketoprofen, nafoxidine hydrochloride, nafcillin sodium, diclofenac, flufenamic acid, and tobramycin) 248 , 252 , 257 , 258 . Owing to their variation in spatial organization and free Gibbs energy, LCs have the potential to improve the dissolution and bioavailability of poorly water-soluble drugs. Furthermore, the tunable nanostructures and dynamic behavior of LCs offer versatile platforms for drug delivery applications to achieve sustained release, enhanced solubility, and targeted delivery of poorly water-soluble drugs 259 , 260 . The resulting SOR ASD tablets demonstrated approximately 50% higher relative bioavailability in dogs compared to the commercial product Nexavar® 286 . Recent studies have shown that liquid‒liquid phase separation (LLPS) plays a crucial role in enhancing the oral absorption of poorly water-soluble drugs. This phenomenon occurs This study highlights that preparation methods and process conditions represent a key consideration in developing amorphous drug-polymer salts, which significantly impact product performance. Figure 32 Amorphous clofazimine-poly(acrylic acid) salts with high stability under tropical conditions and fast dissolution. Reprinted with permission from Ref. 353 Copyright © 2021, The Authors. Figure 32 Salt formation is a practical strategy to improve the aqueous solubility of poorly water-soluble drugs. Nevertheless, its application is inherently limited to ionizable compounds, restricting its broader utility across diverse chemical entities. Investigating disproportionation mechanisms under physiological conditions will also guide formulation strategies to maintain solubility advantages in vivo . Meanwhile, greater emphasis on salt permeability, which is closely linked to solubility, could further optimize the biopharmaceutical performance of poorly water-soluble drugs 362 . Lastly, complex salt systems, such as amorphous salts and polymer salts, hold significant potential for simultaneous enhancements of dissolution rate and stability. 11.