In the past decade potent omics technologies and genome-wide approaches have changed the basic mode of drug discovery and translational research. Full genome sequences of humans and model organisms have allowed development of high-throughput technologies enabling interrogation of entire genomes for gene and protein expression leading to discovery of functional, interactive biological networks. Especially databases linking pathways and disease phenotypes based on clinical and mechanistic data have become indispensable to guide efficient drug discovery and target identification. The recently discovered landmark- or pathway-reporter genes enable discovery of differentially expressed signaling cascades activated by drugs, toxic insults and other stimuli. Strikingly, about 1000 transcripts derived from key nodes of signaling pathways are sufficient to analyze the modulation of 154 human signaling pathways. This significant reduction of data points allows for high-throughput based screens of chemical entities or entire compound libraries to identify mechanisms associated with a clinical phenotype. The archetype of molecular target based approaches in drug discovery may switch to pathway based screening strategies in which the activity and output of an entire pathway rather than a single drug target. Appropriate technologies for such screens have been identified and will be discussed.