Fatigued pilots are prone to experience cognitive disorders that degrade their performance and adherence to high safety standards. In light of the current challenging context in aviation, we report the early phase of our ongoing project on the re-evaluation of human factors research for flight crew. Our motivation stems from the need for aviation organisations to develop decision support systems for operational aviation settings, able to feed-in in the organisations’ fatigue risk management efforts. Key criteria to this end are the need for the least possible intrusiveness and the added information value for a safety system. Departing from the problems in compliance-focused fatigue risk management and the intrusive nature of clinical studies, we report a neuroscientific methodology able to yield markers that can be easily integrated in a decision support system at the operational level. Reporting the preliminary phase of our live project, we evaluate the tools suitable for the development of a system that tracks subtle pilot states, such as drowsiness and micro-sleep episodes.