<p>Perovskite solar cells (PSCs) are a game-changing photovoltaic technology that can be processed from solutions. Molecular engineering of organic A-cations has become paramount to the rapid development of PSCs as they influence the molecular structure of thin films and interfaces. The rich selectivity and designability of organic A-cations offer immense opportunities to regulate various properties of metal halide perovskites (MHPs) through chemical interactions. In this Review, we discuss the roles of organic A-cations in MHPs, providing insight into the structure–interaction–property relationships. We show how the molecular structures of A-cations affect chemical interactions in perovskites, and how these interactions affect the overall properties of PSCs. First, we introduce the impact of organic A-cations and their bonds in MHPs and then explore their roles from the lattice and electronic levels through to crystal growth, stability, defects, charge-carrier transport and band-edge states. Prospects for future research directions, opportunities and challenges are also discussed.</p><p></p>