Since its modest beginnings in support of natural product discovery in the early 1980s, diversity-based high-throughput screening (dHTS) has developed within the pharmaceutical, biotechnology and academic sectors to become one of the most widely used hit identification screening paradigms in early drug discovery. Advances in key component technologies, specifically in diversity collection design, high-throughput assay development and screening informatics, continue to improve the economics and successes of dHTS hit discovery from large screening collections. Through the application of these components in concert, dHTS has evolved from an expensive technology-centric process that was used to screen collections of randomly acquired compounds, into a process that balances chemical, biological and technological inputs to purposefully build diverse compound collections through planned synthesis and purchasing strategies, and that screens these collections efficiently and economically. As a backlash to the 1990s hype that placed the HTS paradigm at the center of attempts to improve overall R&D productivity, sceptics predicted an undignified demise for this approach. Nevertheless, the use of key component technologies in tandem with sophisticated process and quality control systems is now beginning to deliver the success rates promised by the early proponents of the approach. These results indicate that, given continued 'preparedness', dHTS will remain as the principal hit identification tool for early drug discovery well into the next decade.