Systems pharmacology is an emerging approach that sets out to use quantitative concepts rooted in the synergy between modeling and simulation on one hand and large-scale data collection and analysis on the other to investigate biological systems and design therapeutic interventions. Interest in this field has recently increased substantially, but so have perceived challenges and misunderstandings, especially related to implementation. This Commentary explores the opportunities and challenges in the rapidly evolving area of systems pharmacology from a drug discovery and development perspective.