The high sensitivity of cryogenic TES-based detectors opens new windows for astrophysical observations ranging from (far) infrared to X-rays. A number of operational and future space and ground-based instruments rely on cryogenic detectors to improve their performance with respect to the capabilities of earlier technologies. To reach the required sensitivities, base temperatures as low as 50 mK are necessary, and stringent requirements on magnetic shielding, microvibrations, and temperature stability are applicable. To minimize the heat load and complexity of the instruments, efficient multiplexing schemes and low-power amplifiers are needed. In addition, for space-based cryogenic instruments, mechanical launch loads and power consumption limitations constrain the available parameter space for engineering further. This paper discusses the system design considerations which are applicable to optimize the multiplex factor within the boundary conditions as set by the space craft for the X-IFU instrument on the Athena observatory. More specifically, the interplay between the science requirements such as pixel dynamic range, pixel speed, and cross talk, and the space craft requirements such as the power dissipation budget, and available bandwidth will be discussed.