Fluorination of an organic compound affects physicochemical properties, which in medicinal settings perturbs pharmacodynamic, pharmacokinetic, distribution, and/or metabolic profiles both in vitro and in vivo. Thus, the ability to selectively install fluorinated groups under mild conditions is essential for accessing new therapeutics and biological probes. In this field, the Altman group aims to develop innovative reactions, catalyst systems, reagents, and/or strategies for accessing medicinally relevant fluorinated substructures. This specific talk will focus on transition metalcatalyzed and oxidative deoxyfluoroalkylation reactions for accessing medicinally relevant substructures, which converts readily accessible O-based functional groups to fluoroalkyl derivatives that possess distinct physicochemical and biophysical properties that align with druglike characteristics. For many of these transformations, the unique physical properties of fluorinated substructures perturb routine organic reactivity patterns, which necessitates innovative solutions to access target substructures. Additionally, the unique properties of fluorinated substrates enable new reactivity patterns that are not readily achieved by the respective non-fluorinated counterparts, which provides opportunities to develop innovative reactions and strategies for accessing medicinally relevant substructures. These themes will be explored in a series of vignettes involving Cu-catalyzed, Pd-catalyzed, and oxidative aromatization reactions.