How do pharmaceutical companies find new uses for old or failed drugs? Is there a way to 'manage serendipity' at the very first stage of identifying compounds that could be developed into new drugs? Several approaches are now being pursued by various companies that are dedicated to drug repositioning cross a spectrum of technologies and scientific bases. Biochemical markers could provide significant shortcuts for drug development. In this review, we introduce drug repositioning, approaches to it and their associated challenges. We also highlight a novel class of serological biomarkers, namely neo-epitopes, which have proven successful in repositioning drugs in clinical settings