Virtual screening (VS) is an important component of cheminformatics and molecular modeling. An abundance of structural information, indicated by both the ever-increasing availability of 3-dimensional (3D) protein structures and the readiness of free conformational databases of commercially available compounds, such as ZINC, supplies a broad platform for VS. At the same time, new technology enables the implementation of more accurate and sophisticated pharmacophore models and the screening of millions of compounds within a manageable period. Therefore, VS is expected to play a more important role in future drug discovery efforts. This paper will examine and compare the advantages and disadvantages of VS against experimental high-throughput screening (HTS). It will also evaluate pharmacophore-based VS against docking-based VS. The strategies leading to successful pharmacophore-based VS are outlined, including how to enumerate a conformational database efficiently, how to select chemical features for a specific pharmacophore model, how to incorporate excluded volumes to enhance the geographical restrictions, and how to optimize a pharmacophore model. Successful examples of pharmacophore-based VS will be presented.