NASA is currently studying a possible Interstellar Probe mission concept that would venture into the unknown space between our star and other potentially habitable planetary systems. In order to travel out to this distant environment and make scientific contributions in the field of heliophysics, the spacecraft would need to operate for 50 years or more. In designing such a mission, the reliability of the spacecraft and instruments is critical. This paper reviews historical performance of long-lived interplanetary missions and addresses the general approach to assess the reliability concerns for such an undertaking. The approach needs to integrate the understanding of failure mechanisms over time and environmental interactions with a robust fault management system, functionally redundant systems, and a resilient architecture. Included in this approach is the application of probabilistic methods to discern where uncertainties exist and inform a testing campaign to reduce them to an acceptable level of risk.