Today there is a highly elevated demand for synthesis and screening of nature-like biopolymers and their more stable modified derivatives like peptidomimetics because availability of huge amounts of genomic and proteomic data can contribute for research in this area. The design and synthesis of peptidomimetics are most important because of the dominant position peptide and protein-protein interactions play in molecular recognition and signaling, especially in living systems. The design of peptide mimetics can be viewed from several different perspectives and peptidomimetics can be categorized in a number of different ways. Study of the vast literature would suggest that medicinal and organic chemists, who deal with peptide mimics, utilize these methods in many different ways. This manuscript is an endeavor to discuss a variety of methodologies and strategies to develop and establish systematic tools for transformation of peptides into peptidomimetics or further into small drug-like molecules and their pharmacological activities having significance in modern drug design.