Adverse drug events (ADEs) remain a universal problem in drug development, regulatory review, and clinical practice with a substantial financial burden on the global health-care system. Recent advances in molecular and "omics" technologies, along with online databases and bioinformatics, have enabled a more integrative approach to understanding drug-target (protein) interactions, both desirable and undesirable, within a biological system. This has led to the development of systems approaches to risk assessment in an attempt to complement and improve on contemporary observational and predictive strategies for assessing risk. Although still in an evolutionary phase, systems approaches have the potential to markedly advance our understanding of ADEs and ability to predict them. Systems approaches will also move personalized medicine forward by enabling better identification of individual and subgroup risk factors.