<p>Chiral medium-sized rings (MSRs), cyclic molecular structures comprising 7–11-membered rings, are prevalent in bioactive molecules owing to their unique three-dimensional structures and pharmacological properties. Compared with the extensively studied central chirality, MSRs with unconventional chirality — that is, axial chirality, inherent chirality and planar chirality — remain underexplored. The past decade has witnessed rapid advances in this field, with breakthroughs in their synthesis and applications. This Review is structured around the three underexplored types of chirality exhibited in MSRs detailing their key synthetic strategies, with a critical evaluation of their advantages and limitations. Additionally, the factors that influence the conformational stability of chiral MSRs are discussed using structure and energy analysis.</p><p></p>