The changes in screening philosophy over a 40 year period from in vivo phenotypic screening to a reductionist mechanism-based in vitro search for a single selective compound against a single target are described. Examples are given of the shortcomings of the reductionist paradigm and the advantages of the phenotypic and multi-target screening approaches towards drug discovery and repurposing. Non-mechanism biased phenotypic screening offers the advantages of enhanced target opportunity space and is a good match for screening of ligands covering narrow chemistry space, e.g. natural products. Retrospective analysis suggests that phenotypic screening is better than mechanistic screening in finding first in class compounds, particularly for the more complex disease targets.