The term high-throughput screening (HTS) was unknown to the scientific literature until the mid-1980s, but it has undergone rapid evolution in the past 30 years. The HTS enables pharmaceutical companies to compete in the ‘new-drug invention race’ in the current era, as HTS provides screening of >1,00,000 compounds per day using microplates and various automated robotic systems. The core step involved in the development of a successful HTS campaign involves the implementation of the correct ‘assay’. HTS assays can be functional or non-functional assays. Another aspect of HTS is the development and maintenance of compound libraries. Compound libraries are growing steadily now by acquiring data on all the medicinal chemistry molecules, using combinatory-chemistry methods, and purchasing compound collections from library vendors, academia, etc. The main technical aspects of HTS involve automation mode, plate storage systems, robotic arms, and detection assays. Similar to HTS, the computer-aided drug design (CADD) field has also grown significantly and is employed parallelly with HTS in the early phases of drug development. CADD utilizes both structure and ligand-based drug design methods. Various commercial computational codes are available for these CADD approaches. This chapter reviews the various technical aspects of HTS and CADD in detail.