In addition to high-throughput screening (HTS), the main lead discovery technology employed by most pharmaceutical companies today is virtual screening (VS). Although the two techniques have somewhat different philosophical origins, they contain many synergies that can potentially enhance the lead discovery process. Here, we describe many of the latest developments in VS technology with particular emphasis on their potential impact on HTS in, for example, focussed screening and data mining. In addition, we highlight key issues that need to be addressed before the potential of such efforts can be fully realized.