The state-of-the-art electro-optical sensors being designed for today's space-based environmental applications require a complete characterization and thorough calibration. This is especially true for sensors designed to assess global climate change, which require very small uncertainties. This paper describes a system-level approach that addresses each phase of calibration, from planning to on-orbit operations. This approach encourages early planning and continuity of effort throughout the lifetime of the project (pre- and post-flight) to promote an optimum calibration approach that will minimize uncertainty for the intended application. This paper also discusses considerations for component level characterization, ground calibration and standards, in-flight calibration sources and trending, and in-flight validation assessment.