Novel technologies are emerging for high-throughput screening, driven by the needs and fine-tuning of established drug discovery activities, as well as by the emergence of novel target classes resulting from the deciphering of the human genome. Disciplines other than biology have now entered the screening scene, as bioinformatics, micro-technology and analytics provide powerful methodologies and applications that were not previously suitable for high-throughput screening. Many of these will move high-throughput screening from a numbers game to a content- and information-based approach to identify leads for novel disease targets.