In this article, Jose´ L. Medina-Franco, Marc A. Giulianotti,Gregory S. Welmakerand Richard A. Houghten review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and high-throughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target–one drug model to a multiple-target approach.