It is well documented in the literature that ****** receptors modulate a large number of physiological functions (pain perception, breathing, mood, gastrointestinal motility, etc.). Natural ******* and 4,5α-epoxymorphinan derivatives obtained by their chemical modifications, which are frequently referred to as semi-synthetic opioids, are among the most important types of ****** ligands. On the other hand, fluorinated compounds have a remarkable record in medicinal chemistry providing developmental candidates for therapeutic applications. The reasons are very similar steric impacts of hydrogen and fluorine along with the influence of substituting fluorine for hydrogen in the molecules of exogenous compounds on their lipophilicity, metabolism, conformation and other properties. This review focuses on the functionalization of 4,5α-epoxymorphinans and their derivatives via substitutions with fluorine or fluorine-containing groups in the search for improved pharmacological profile ****** ligands and ¹⁸F-containing ****** receptor radioligands for PET. These functionalizations are typically associated with substituents either at the C(3)–O, C(6)–O, and N(17) positions of the 4,5α-epoxymorphinan core or at C(7) in the thebaine based Diels–Alder type adducts. The syntheses resulted in the preparation of both single fluorinated derivatives or short sets of fluorinated derivatives and the families of fluorine-containing opioids allowing, in principle, the structure–activity relationship studies.