The long-term goal for international safeguards is to transition to unattended, near real-time verification. To support this goal, the International Atomic Energy Agency (IAEA) has requested new technologies for process monitoring and near real-time accountancy. As has been shown in other industries, at-line process monitoring is a method by which the international community could meet the IAEA’s stated goals by automating in-process sampling and analysis. By integrating automation, high-throughput sampling and analysis, advanced analytics and machine learning, and cross-validation using multiple different near real-time techniques, it should be possible to achieve unattended near real-time accountancy with overall uncertainty levels comparable to, or better than, current off-line approaches. This paper endeavors to properly define at-line process monitoring as applied to safeguards and will discuss researchers’ findings on the potential role of automated sampling-based measurements to meet safeguards near real-time accountancy and process monitoring needs. Furthermore, the authors hope this paper initiates a conversation on the values of at-line process monitoring as a grander part of the international safeguards regime.