The large-scale application of combinatorial chemistry to drug discovery is an endeavor that is now more than ten years old. The growth of chemical libraries together with the influx of novel genomic targets has led to a reconstruction of the drug-screening paradigm. The drug discovery industry faces a post-genomic world where the interplay between tens-of-thousands of proteins must be addressed. To compound this complexity, there now exists the ability to screen millions of compounds against a single target. This review focuses on the practice and use of selecting individual compounds from large chemical libraries that act on targets relevant to signal transduction.