Abstract: Small molecular drugs with large ring structure have recently attracted the attention in medicinal chemistry, the reason is their advantages in improving pharmacological activity and selectivity, and in satisfying drug-like properties. The macrocyclic structure takes into account both the microscopic structure for binding to targets and the macroscopic properties required by the pharmacokinetics. Although macrocyclic drugs historically originated from natural products, in recent years, they have been successfully designed, expanded the chemical space of traditional small molecules, and, to some extent, broken through the well-known the Role of Five in drug innovation. In addition, macrocyclic molecules also pave the path for developing drugs for non-druggability targets and for interfering with protein-protein interaction. This article focuses on the molecular design of macrocyclic drugs with some successful examples, concisely discusses structural optimization of a few macrocyclic natural drugs, and briefly describes stapled peptides in medicinal chemistry.