Drug repositioning is an innovation stream of pharmaceutical development that offers advantages for drug developers along with safer medicines for patients. Several drugs have been successfully repositioned to a new indication, with the most prominent of them being viagra and thalidomide, which have generated historically high revenues. In line with these developments, most of the recent articles and reviews on repositioning are focused on success stories, leaving behind the challenges that repositioned compounds have on the way to the clinic. Here, I analyze repositioning as a business opportunity for pharmaceutical companies, weighing both challenges and opportunities of repositioning. In addition, I suggest extended profiling as a lower-risk cost-effective repositioning model for pharmaceutical companies and elucidate the novel collaborative business opportunities that help to realize repositioning of shelved and marketed compounds.