Layer-structured Ruddlesden–Popper (RP) perovskites (RPPs) with decent stability have captured the imagination of the photovoltaic research community and bring hope for boosting the development of perovskite solar cell (PSC) technology. However, two-dimensional (2D) or quasi-2D RP PSCs are encountered with some challenges of the large exciton binding energy, blocked charge transport and poor film quality, which restrict their photovoltaic performance. Fortunately, these issues can be readily resolved by rationally designing spacer cations of RPPs. This review mainly focuses on how to design the molecular structures of organic spacers and aims to endow RPPs with outstanding photovoltaic applications. We firstly elucidated the important roles of organic spacers in impacting crystallization kinetics, charge transporting ability and stability of RPPs. Then we brought three aspects to attention for designing organic spacers. Finally, we presented the specific molecular structure design strategies for organic spacers of RPPs aiming to improve photovoltaic performance of RP PSCs. These proposed strategies in this review will provide new avenues to develop novel organic spacers for RPPs and advance the development of RPP photovoltaic technology for future applications.