After more than two decades of research focused on care transition improvement and intervention development, unfavorable outcome measures associated with care transitions across healthcare settings persist. Readmissions rates remain an important outcome to target for intervention, adverse events associated with care transitions continue to be an issue, and patients are often dissatisfied with the quality of their care. Currently, interventions to improve care transitions are disease specific, require substantial financial investments in training allied healthcare professionals, or focus primarily on hospital-based discharge planning with mixed results. This complex situation requires a method of evaluation that can provide a comprehensive, in-depth, and context-driven investigation of potential risks to safe care transitions across healthcare settings, which can lead to the creation of effective, usable, and sustainable interventions. A systems' approach known as Human Factors and Ergonomics (HFE) evaluates the factors in a system that affect human performance. This article describes how HFE can complement and further strengthen efforts to improve care transitions.