Halogen atoms have been at the center of many rational medicinal chemistry applications in drug design. While fluorine and chlorine atoms are often added to enhance physicochemical properties, bromine and iodine elements are generally inserted to improve selectivity. Favorable halogen interactions such as halogen bond have been thoroughly studied through quantum mechanics and statistical analyses. Although most of the studies focus on halogen interaction through its σ-hole, hydrogen bonding also has a significant impact. Here, we present an analysis describing the interacting environment of halogen atoms in protein−ligand context. With consideration of structural redundancy in the PDB, tendencies toward specific molecular interactions consideration have been refined and implications for rational drug design with halogens further discussed. Finally, we highlight the moderate occurrence of halogen bonding and present the other roles of halogen in protein−ligand complexes, completing the medicinal chemistry guide to rational halogen interactions.