Cultural heritage assets constitute a fundamental socioeconomic resource, but the actual works of art need to be maintained, counteracting degradation processes, to transfer these benefits to future generations. In particular, the removal of soil, aged coatings, and vandalism/overpaints is one of the most needed interventions in art restoration. Traditional cleaning methodologies, based on classical solution and polymer chemistry, only grant limited control of the cleaning interventions, with the risk of affecting the original components of the artifacts, and often involving the use of toxic or non-environmentally friendly compounds. Alternatively, materials science, colloids, and soft matter have provided valuable and safe solutions in the last decades. This review provides a selection of the most recent and advanced methodologies for the wet cleaning of works of art, spanning from nanostructured cleaning fluids (microemulsions, surfactants swollen micelles) to physical and chemical gels. The new methodologies work on different physico-chemical mechanisms, such as processes for detaching/dewetting, to selectively remove the unwanted layers in sustainable and cost-effective interventions. The best performing systems, like microemulsions confined in “twin-chain” polyvinyl alcohol gels, have been assessed in the cleaning of masterpieces such as works by Pablo Picasso, Jackson Pollock and Roy Lichtenstein. Particular attention is dedicated to “green” chemistry systems, using low-toxicity solvents or bio-based/waste materials to build gel networks. Finally, current trends and future perspectives are given, showing that advanced systems for art cleaning link with transversal fields of crucial importance even beyond Cultural heritage conservation, e.g., detergency, tissue engineering, drug-delivery, food industry and cosmetics.