Developing new drugs for human diseases is increasingly expensive, time-consuming, and risky. To this, the application of computer-aided drug design (CADD) plays a crucial role in finding and constructing new drugs. The role of CADD and its various approaches are based on the available chemical libraries that contain millions of compounds. This information opens the way for structure-based (SBDD) and ligand-based drug design (LBDD) methods. Among these methods, LBDD has been one of the most popular approaches in drug discovery and lead compound optimization, which proved to be useful in the absence of three-dimensional (3D) structures of potential drug targets, facilitating the development of pharmacologically active compounds that bind with the biological target of interest. However, the successful completion of a drug discovery project without any impediments needs the usage of a better and more comprehensive ligand database for drug design. Several ligand databases have emerged in the last few years supplying platforms to guide users in screening publicly accessible chemical databases in a reasonable time. Screening libraries continue to evolve as researchers gain a greater appreciation of the suitability of small molecules for specific biological targets, processes, and environments. Hence, in order to highlight their relevance in modern drug discovery programs, we present this chapter spotlighting various databases beneficial for LBDD. Inclusively, it will also briefly touch upon some mainstream LBDD approaches that changed the way new drugs were explored and identified.