Structural fine-tuning of organic semiconductors by side-chain modifications is indeed an important factor in enhancing the efficiency of organic solar cells (OSC). In this review, we recapitulate the recent efforts on side chain engineering of organic small molecules and their effect on molecular packing, crystallinity, charge transport, and solar cell properties. The influence of the length and branching position of side-chains on device performance are comprehensively discussed. The challenges and prospects of structural manipulations at the molecular level are discussed, with a focus on their relevance to the future technology of OSCs.