The designing of chemical libraries is a major component of the drug discovery process, with high throughput screening of libraries enabling the identification of lead compounds for further investigation and development. Not long after this paradigm of chemical library synthesis and in vitro screening was introduced, there was incorporation of computational methods for the generation of initial chemical libraries and in silico screening. For the generation of chemical libraries, fragment based and combinatorial approaches have historically been employed, whereas structure-based approaches have been used for initial computational screening. While in silico approaches to the discovery processes have become institutional mainstays with various established workflows, researchers continue to pursue novel computational methods for optimizing the generation, screening, and work-up of chemical libraries.