As new treatments are becoming more specialized, optimizing real-world value is critical. With the recent re-emergence of outcomes-based contracts, quantifying the real-world drivers of effectiveness is essential in order to make informed decisions. We describe state-of-the-art methods to characterize those drivers and predict effectiveness. As clinical programs now reflect the reality of new specialized treatments, we must improve upon our ability to predict how the availability of these new clinical programs will impact health plan population clinical outcomes, disease burden, and costs. In addition to a treatment’s demonstrated clinical efficacy, the demographic characteristics, utilization factors, population health factors, as well as system and health plan circumstances, all collectively comprise the determinants or drivers of real-world effectiveness. As such, we must make the best use of available data and emerging modeling methodologies in order to better inform decision makers’ choices. We will discuss the emerging approaches to such questions via practical examples and debate the merits of the various approaches.