Cell-based screens represent one of the most venerable approaches to lead generation, indeed, antimicrobial screens were the mainstay of drug discovery in the 1940s, 1950s, and 1960s (1 ). However, cellular assays also represent one of the most dynamic areas of innovation in high-throughput screening (HTS). The driver of this innovation is the demand for more leads from more complex targets. Genomics discovery efforts have generated many potential targets for HTS, but the biochemical nature of these novel targets may not be elucidated prior to their entry into the lead generation process. Therefore, these targets are frequently addressed in “gene to screen” paradigms that rely on cellularscreening approaches. Advances in cell-based screening approaches have also been driven by the need to address complex, multi-component target classes that may not be feasible in biochemical assays. Finally, the increasingly combative intellectual property playing field, and the need to accelerate the drug discovery process have driven innovations in cell-based screening methodologies.