DPP-4 specifically degrades the incretin hormone GLP-1 and GIP, both of which are vital modulators of blood glucose homeostasis. Attributed to its potential biological function, DPP-4 inhibition has presently represented an attractive therapeutic strategy for treating diabetes and aroused a significant interest in the pharmaceutical industry. Chemical stability, selectivity and pharmacokinetic properties have been continuously emphasized during the long journey of R&D centered on DPP-4 inhibitors. The current landscape of the development of DPP-4 inhibitors is outlined in this review, with a focus on rational drug design and structural optimization to pursue chemical stability, selectivity and favorable pharmacokinetic properties. In addition, the structure-activity relationships, based on reported DPP-4 inhibitors, will be discussed.