This paper discusses the particular system and spacecraft design issues associated with a sample return mission to the relatively unknown environment of a comet. The required characteristics of the design - robustness, adaptability and autonomy - are described in relation to the three major phases in the evolution of our knowledge about the comet properties i.e. before launch, during the comet observation phase and during the landing/on-comet operations. The classification of comet characteristics into observable and non-observable parameters is used to identify the respective responsibilities of the ground control station and the space segment. The requirement for on-board autonomy during the landing and on-comet operations is shown to have a significant impact on the spacecraft design and imposes specific requirements on the comet kinematic, dynamic and surface models. To illustrate, in a practical way, the important relationship between comet models and spacecraft design, the paper presents various technical solutions that were developed to cope with the autonomy requirements. The autonomous control system to stabilise the spacecraft touch-down dynamics is analysed and the autonomous measurement system, required to detect and damp spacecraft motion on the comet surface, is described. In order to operate in the potentially dusty environment of a comet, this measurement system uses only inertial sensors. Numerical results illustrate the performance of this autonomous system as a function of the comet surface characteristics. It is shown that, in some cases, maintaining the spacecraft stability could become very costly in propellant if anchoring does not take place immediately after touch-down. Finally, a method to determine autonomously the three-axis attitude of the spacecraft on the comet, also using inertial sensors and on-board comet models, is analysed. Numerical results show that this method could allow the autonomous pointing of the antenna and the recovery of the Earth communication link when optical sensors are not available.