With the advent of "intelligent" polymeric systems, the use of stimuli-responsive in situ gelling systems has been revolutionized. These interesting polymers exist as free-flowing aqueous solutions before administration and undergo a phase transition to form a viscoelastic gel in a physiological environ through various stimuli such as temperature, pH, solvent, biochemical, magnetic, electric, ultrasound, and photo-polymerization. These smart polymers are endowed with numerous merits such as ease of administration, sustained release, reduced frequent administration with improved patient compliance, and targeted and spatial delivery of a drug with reduced frequency of side effects. Concerted efforts are being made to modify these polymers synthetically because they hold immense potential in various fields such as polymer chemistry, materials science, pharmaceutics, bioengineering medicine, and chemical engineering. In addition to novel drug delivery, these smart polymeric systems have exhibited tremendous applications in tissue engineering, regenerative biomedicine, molecular imprinting, cancer therapy, gene delivery, theranostic and other applications. The current review mainly focuses on the fundamental principles involved during in situ gelling, use of various "smart" drug-delivery formulation systems through diverse routes for their administration, as well as their well-documented biomedical applications. The pertinent literature, marketed formulations, and recent advances on these stimuli-responsive sol-gel-transforming systems are also discussed.