We show that crystallographic compatibility, quantum yield, and fatigue resistance are three important factors that diarylethene (DAE) should simultaneously satisfy to realize high-performance photoprogrammable polymer field-effect transistors (FETs). The enhancement of crystallographic compatibility achieved by locating DAE preferentially in the vicinity of intercrystallite tie chains is mainly dependent on the overall molecular volume of DAE. The quantum yield of DAE for photocyclization is dependent on the molar portion of the photoactive antiparallel conformer, while photocycloreversion is determined by both the aromatic stabilization energy of the closed isomer and allowed free space for each DAE molecule. While the chemical resistance of DAE relies entirely on its chemical structure, the electrical fatigue resistance of DAE-embedded FET depends on both the morphological/structural environment of the DAE/polymer blend and chemical resistance of the DAE molecule. To precisely control each of these determining factors of DAE-embedded polymer FETs, a series of DAE is synthesized and systematically analyzed. High-mobility DPPDTT is blended with various DAE derivatives as a matrix polymer. We show that strategic substitution of functional groups at the specific reaction site of DAE can lead to an ideal molecular switch for high-performance photoprogrammable polymer FETs with high photoprogrammable switching ratios of 4405, as well as high electrical fatigue resistance of up to 100 photoprogrammable switching steps. The physics behind the success of the optimized DAE structure is discussed using the results from various analysis techniques. We shed light on how the crystallographic compatibility, quantum yield, and fatigue resistance of DAE can vary with and be optimized by chemical modification of the DAE reaction site.