DprE1 is a crucial enzyme involved in the cell wall synthesis of Mycobacterium tuberculosis and a promising target for antituberculosis drug development. However, its unique structural characteristics for ligand binding and association with DprE2 make developing new clinical compounds challenging. This review provides an in‐depth analysis of the structural requirements for both covalent and non‐covalent inhibitors, their 2D and 3D binding patterns, as well as their biological activity data in vitro and in vivo, including pharmacokinetic information. We also introduce a protein quality score (PQS) and an active‐site map of the DprE1 enzyme to help medicinal chemists better understand DprE1 inhibition and develop new and effective anti‐TB drugs. Furthermore, we examine the resistance mechanisms associated with DprE1 inhibitors to understand future developments due to resistance emergence. This comprehensive review offers insight into the DprE1 active site, including protein‐binding maps, PQS, and graphical representations of known inhibitors, making it a valuable resource for medicinal chemists working on future antitubercular compounds.