The large-scale use of toxic and environmentally hazardous solvents remains a major challenge in industrial manufacturing and consumer-goods production. Conventional solubilization processes often depend on harsh conditions, including elevated temperatures and pressures, resulting in high energy consumption, health risks, and environmental pollution. Developing sustainable alternatives is therefore an urgent scientific and societal priority. This article discusses recent advances in green solubilization and emerging strategies aiming to reconcile efficiency with environmental compatibility. We address the future role of classical and “green” solvents, including ionic liquids (ILs) and natural deep eutectic solvents (NADES), and critically assess their benefits and limitations from a sustainability perspective. Particular emphasis is placed on water as the potentially “greenest” solvent, highlighting how its intrinsic tendency to form structured, heterogeneous environments can be advantageous or detrimental for solubilization. In this context, we examine mesoscale structuring, surfactant-free microemulsions, and dynamic interfaces. Furthermore, naturally derived solubilizers such as hydrotropes, biosurfactants, and proteins are considered promising tools to enhance solubility while maintaining biocompatibility and low environmental impact. Selected examples from our own work illustrate how combining water-based structuring with bio-derived or benign additives can create new pathways toward energy-efficient and sustainable solubilization technologies.