The compelling demand for higher performance and lower cost in the optoelectronics industry has driven the development of organic semiconductors. Molecular crystalline semiconductors (MCSs), especially two-dimensional MCSs (2D-MCSs), possess intrinsic ordered structure, quantum confinement effect, high mobility, unique optical and electrical properties, and more ecological and cheaper production, which make great promises in high-performance optoelectronic applications. Here we provide a review of design principles and synthetic strategies for 2D-MCS materials, exploiting their potential as a revolution option in associated optoelectronic devices. The merits and limitations of each strategy are presented, and these molecular crystals are considered as a competitive choice for emerging semiconducting materials in information science. Finally, the current challenges and future perspectives in this field are also elaborated.