There is profound interest that has been generated of using ionic liquids as soluble supports for the immobilization of either catalyst or reagent and organic synthesis in a homogeneous medium. Availability of abundant varieties of ionic liquids provides opportunities for their use as soluble supports well suited with most established chemistries. The solubility of ionic liquids can be fine-tuned by altering cations and anions that allow them to phase separate from the aqueous medium and less polar solvents. A less polar solvent is added to the reaction mixture containing the ionic liquid-supported species after executing the desired reaction, and the ionic liquid phase is separated from the organic phase. At the end of the reaction, the ionic liquid-supported catalysts and reagents can be regenerated or reused. Due to these advantages, combinatorial libraries of small molecules of potential interest, oligopeptides, and oligosaccharides were synthesized using ionic liquid-supported synthesis (ILSS). Further, this chapter highlights the various applications of ionic liquid as support for the catalyst, reagent, and substrate for organic synthesis along with comparing with solid phase, soluble polymer-supported, and fluorous phase approaches. © 2020 Elsevier Inc. All rights reserved.