The last two decades have witnessed tremendous growth in the area of organic transformations mediated by organocatalysts. Among them, proline and related catalysts have been extensively studied for a variety of reactions. In this chapter, the main emphasis is laid on proline and proline-derived catalysts for C-O, C-N, and C-S bond formation leading to various five-membered, six-membered, and polycyclic heterocycles. Synthesis of nitrogen-containing compounds includes quinoline, pyridine, and pyrimidine framework followed by imidazole, phthalimide, pyrrole, indole, and triazole derivatives. The synthetic utility of proline catalyst is further discussed in the construction of indolizidine, pyrrolizidine, and quinolizidine framework. Its application to the synthesis of various natural products particularly hydroxylated alkaloids is described. Synthesis of oxygen-containing compounds mediated mainly by proline and related catalysts involves the furan, pyran, and hexose derivatives with its further application in the synthesis of natural products related to the lactone and flavones derivatives. The last section of the chapter mainly covers sulfur-containing heterocycles followed by miscellaneous reactions catalyzed by proline and proline-derived catalysts. © 2021 Elsevier Inc. All rights reserved.