**Abstract**

Chemical biology is the scientific discipline that deals with the application of chemical techniques and often small molecules produced through synthetic chemistry, to the manipulation and study of biological systems. Its working framework ranges from simple chemical entities to complex drugs by employing the principles of biological origin. This chapter particularly focuses on the principles and working models of chemical biology to discover new drug leads. Drug discovery is an extensive and multifaceted complex process. Chemical biology uses both natural and synthetic compounds with the best therapeutic potential and verifies them by employing the best possible chemical toolsets. Screening of compounds is done by the use of phenotypic as well as the target-based screening to identify and characterize the potent hits. After the identification of target, it is characterized, and validated by extensive testing. The next step is the validation of hits obtained, and lead compounds are tested in clinical trials before introducing them for commercial application.

**Keywords:** chemical biology, drug discovery, target identification, target validation, phenotypic screening
