<div>Autonomous vehicle technologies have become increasingly popular over the last few years. One of their most important application is autonomous shuttle buses that could radically change public transport systems. In order to enhance the availability of shuttle service, this article outlines a series of interconnected challenges and innovative solutions to optimize the operation of autonomous shuttles based on the experience within the Shuttle Modellregion Oberfranken (SMO) project. The shuttle shall be able to work in every weather condition, including the robustness of the perception algorithm. Besides, the shuttle shall react to environmental changes, interact with other traffic participants, and ensure comfortable travel for passengers and awareness of VRUs. These challenging situations shall be solved alone or with a teleoperator’s help. Our analysis considers the basic sense–plan–act architecture for autonomous driving. Critical components like object detection, pedestrian tracking, trajectory planning, and teleoperation are analyzed, and concepts for overcoming the challenges mainly in these components are presented.</div>