The increasing debate regarding the predictiveness of rodent persistent pain models for clinical efficacy has spurred rapidly evolving numbers and types of novel models from which to choose. While several excellent reviews of these models have been published in recent years, few focus on their specific applications and particular challenges with the use of these models in the setting of drug discovery. Thus, in this review, how models of persistent pain may be used to: 1) screen molecules for in vivo efficacy, 2) advance lead compounds and 3) guide decision making for clinical trial design is discussed. Relative to other disease areas for potential drug discovery and development, chronic pain appears to be well-poised for drug discovery and development. This is in large part due to the advanced understanding of pain mechanisms and the upsurge in the development of novel, specialized rodent models of persistent pain and improvements in methods of pain assessment in animals.