Small molecules with potent and selective antitumor activity continue to be identified by screening in cellular assays and to be entered into clinical development, and in some cases small molecules are progressed despite the fact that the mechanism of action is unknown. Current examples of drugs with unknown mechanism of action include LY-573636 (Eli Lilly & Co), CHS-828 and SPC-595 (Sunesis Pharmaceutical Co Ltd). Early discovery and the elucidation of structure-activity relationships may be in part facilitated by the fact that the compounds must be relatively soluble and permeable to cells to demonstrate activity, although the challenges of optimizing absorption, distribution, metabolism and excretion/pharmacokinetic properties, toxicity and clinical activity remain similar to compounds developed under the 'targeted therapy' paradigm.