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High-throughput screening (HTS) is a well-established, hit-finding approach used in the pharmaceutical industry. In this article, we discuss recent experience at Novartis with respect to factors influencing the success of HTS campaigns. An inherent measure of HTS quality could be defined by the assay Z and Z'factors, the number of hits and their biological potencies; however, such measures of quality do not always correlate with the advancement of hits to the later stages of drug discovery. Also, for many target classes, such as kinases, it is easy to identify hits, but, as a result of selectivity, intellectual property and other issues, the projects do not result in lead declarations. In this article, HTS success is defined as the fraction of HTS campaigns that advance into the later stages of drug discovery, and the major influencing factors are examined. Interestingly, screening compounds in individual wells or in mixtures did not have a major impact on the HTS success and, equally interesting, there was no difference in the progression rates of biochemical and cell-based assays. Particular target types, assay technologies, structure-activity relationships and powder availability had a much greater impact on success as defined above. In addition, significant mutual dependencies can be observed–while one assay format works well with one target type, this situation might be completely reversed for a combination of the same readout technology with a different target type. The results and opinions presented here should be regarded as groundwork, and a plethora of factors that influence the fate of a project, such as biophysical measurements, chemical …