Autonomy is used on spacecraft for minimizing operational cost and providing onboard failure response. System studies have been performed to provide spacecraft design criteria. This paper presents the design drivers and recommended design criteria for the Data Handling Subsystem (DHS). The impact of interfacing spacecraft subsystems, as well as alternate solutions, is discussed. The importance of establishing detail processing requirements through a Failure Modes and Effects Analysis (FMEA) is addressed and related to various spacecraft computer capabilities. A prioritized list of DHS design topics is included.