The use of fluorine-18 (¹⁸F) has had an important impact in medicine since its discovery. Fluorine-18 is the most commonly used isotope in positron emission tomography (PET), which is a noninvasive and sensitive radionuclide-based molecular imaging technology. PET can be used for diagnosis, staging, therapy planning, treatment control, and drug development. Fluorine-18 has ideal nuclear properties for PET, resulting in high resolution, accessibility, and marketability. Furthermore, its nuclear properties result in a low patient radiation burden. From a chemical point of view, fluorine-18 is rather difficult to work with. The fluoride-18 anion possesses limited nucleophilicity. Thus, its chemical applicability is restricted. On the other hand, fluorine-18 gas leads to products with low molar activity (A_m), and only a few biological applications can be imaged with low A_m. This chapter will provide a broad overview of fluorine-18 chemistry, an in-depth description of challenges, and possible solutions for producing 18F-bioactive molecules and highlight the clinical applicability of the described synthetic strategies. Finally, the chapter will conclude with a critical analysis of the field and provide some considerations moving forward.