Increasingly, the pharmaceutical industry has been plagued with escalating costs coupled with decreasing productivity, leading to speculation that the pharmaceutical business model as we know it may be broken. It is in this context that many in the industry have been searching for innovative strategies to reduce cost as well as risk. Both phenotypic screening and drug repositioning represent discovery approaches that fit this description. Melior Discovery is unique among drug discovery organizations in its use of an in vivo phenotypic screening platform used to reposition discontinued clinical-stage compounds. The story of Melior's lead candidate, MLR-1023, illustrates this approach. We show that when dealing with “privileged” substrate (discontinued clinical-stage compounds that exhibit good human safety and tolerability characteristics and other favorable drug-like characteristics), an in vivo screening platform, comprising a wide array of animal models of human disease, is ideal. Many years of conducting these screens on hundreds of compounds has shown the frequency with which otherwise unpredicted therapeutic potential is associated with drug targets that were thought to be well-characterized.