Civil and military unmanned aircraft systems (UAS) operations are currently subject to restrictions that put major limits on their use of airspace. There is considerable debate about how to develop the safe, secure and efficient integration of UAS into non-segregated airspace and aerodromes. This paper examines a necessary safety aspect. Airlines and their passengers would obviously ask, “Is it still safe with all these unmanned aircraft around?” The spotlight must be on Air Traffic Control Systems as High Reliability Organizations (HRO). That status comes from industry characteristics: focus on safety, effective use of technological improvements, learning from feedback from accidents/incidents, and an underpinning safety culture. The safety of ATC Systems has improved dramatically: accidents are now the product of rare and complex ‘messes’ of multiple failures. It is therefore a major challenge to preserve the HRO status by ensuring at least current safety performance. The analysis sketches feasible processes of policy decision-making and safety analyses. Key factors are policies on UAS equipage and airspace usage, implementation of a Traffic Alert and Collision Avoidance System (TCAS)-variant appropriate for UAS, use of an ‘Equivalent Level of Safety’ philosophy, small datalink latencies, proven HRO safety and learning cultures, and stress testing of system resilience by real-time simulations.