The Cassini spacecraft consists of 12 instruments: 4 Optical Remote Sensing Instruments (ORS), 6 In-situ observation instruments to study Magnetospheric and Plasma Science (MAPS), one Radar instrument, and one Radio Science (RSS) instrument. When this complex mission was initially architected, much of the early emphasis was placed on the spacecraft function and design, rather than operations. The spacecraft and mission design posed significant challenges to the science and sequence development process for the four-year tour of the Saturnian system.The science planning and sequence development process produces a comprehensive set of commands for all science and engineering activities for an approximate 40 day time period. The end-to-end sequence design process consists of five phases: 1) Integration of the Science Operations Plan (SOP), a high-level plan of science and engineering activities, detailing their timing, power, thermal, data volume, and pointing profiles 2) SOP Implementation, in which resource conflicts are resolved and activities constraint checked 3) Aftermarket and SOP Update, in which the SOP is updated while in tour using the latest information on the navigation ephemeris, and the spacecraft's and instruments' performance 4) Science and Sequence Update Process, which results in an integrated, validated, uplinkable, and flyable distributed sequence 5) Execution, which includes system-level and instrument-internal real-time commands, anomaly response, and sequence pointing and timing adaptation using the latest ephemeris information Each phase of the sequence development process had to overcome many operational challenges due to the immense complexity of the spacecraft, tour design, pointing capabilities, flight rules and software development. This paper will address the specific challenges related to each of those complexities and the methods used to overcome them during operations.