Polymers are large, chain-like molecules made of recurrent structural units (monomers), providing versatility and biocompatibility for diverse applications. In situ gelling systems depict an innovative technique for drug delivery, utilizing the exclusive properties of polymers to transform from a liquid (sol) to a gel state under physiological conditions. This chapter studies the mechanisms driving in situ gel formation, focusing on the properties of polymers driving such transformation. These polymers respond to environmental impetus, like pH, temperature, ionic strength, and enzymatic activity, enabling concise and controlled drug release. The discussion emphasizes the classification of in situ gelling systems based on their triggering mechanisms—pH-responsive, temperature-responsive, ion-activated, and enzyme-responsive gels—and their applications in pharmaceuticals, biomedicine, and tissue engineering. By means of practical applications and case studies, this chapter demonstrates the adaptability and advantages of in situ gels, including enhanced bioavailability, minimized side effects, and enhanced patient compliance. Overall, it highlights the potential of these intelligent, polymer-based platforms as advanced solutions for targeted and sustained therapeutic delivery.