For financial and operational reasons many aircraft manufacturers are working on the development of single-pilot commercial aircraft. It is suggested that cargo operations may commence in the early 2030s followed by passenger flights later that decade. Two technological approaches for the development of single-pilot airliners are being developed either based upon extant technology and operating concepts derived from uninhabited aviation systems and military aircraft, or alternatively based upon high levels of onboard autonomy/automation. This review considers the economic, technological, regulatory (safety) and societal acceptance of the single-pilot airliner, and examines some of the operational challenges that airlines may face. It is suggested that while the technological and safety challenges may be resolved, it is the operational challenges that may determine if the concept is ultimately viable.