The positron-emitting radionuclide fluorine-18 plays a prominent role in radiopharmaceuticals for positron emission tomography (PET) due to its favourable nuclear decay properties. Depending on the production method, 18F can be obtained in two different chemical forms: electrophilic [18F]fluorine gas and nucleophilic [18F]fluoride. Nucleophilic [18F]fluoride exhibits several advantages with respect to accessibility and chemical handling. Therefore, nucleophilic 18F-substitution reactions are of pivotal importance for the production of PET radiotracers. This chapter is devoted to this class of reactions, and in the following pages, we seek to provide a general overview of 18F itself as well as insights into nucleophilic 18F-substitution reactions. More specifically, the prerequisites for this reaction with regard to solvent, leaving groups, reactants, etc. are examined. Furthermore, several examples are discussed which demonstrate the potential of this reaction to create highly clinical relevant PET tracers. Finally, this chapter also provides practical tips and tricks for those performing this reaction in the laboratory.