Assay formats and screening technologies can deliver more than one readout per measurement and therefore can be considered to be information-rich. This holds true for biophysical and selected biochemical assays, and in particular for cellular assay formats, where the term 'high-content assay' describes the most complex and advanced paradigm of small-molecule screening available to date. Given the multifactorial nature of the lead generation and optimization process in drug discovery, the enhanced information-density offered by multiplex screening technologies is considered to be beneficial to an informed hit selection for optimization. While hard evidence for an enhancement in hit and lead selection is only now emerging, multiplexed screening technologies will fulfill their promise in drug discovery if our understanding of target pharmacology and the complexity of biological systems can be advanced in parallel.