The identification of reliable, general, and high yielding methods for the formation of C(sp2)-fluorine bonds remains a major challenge for synthetic organic chemists. A very common approach involves nucleophilic aromatic fluorination (SNAr fluorination) reactions of aryl chlorides or nitroarenes. Despite being known for more than a century, traditional SNAr fluorination reactions suffer from significant limitations, particularly on a process scale. These include the high cost of common reagents [e.g., cesium fluoride (CsF)], a requirement for elevated temperatures and long reaction times, poor functional group tolerance, and the need for rigorous exclusion of water. This Account summarizes our collaboration with Corteva Agriscience (previously Dow Agrosciences) to address many of these challenges. This collaboration has provided a platform for fundamental scientific advances involving the development of new methods, reagents, and substrates for mild and high yielding nucleophilic fluorination reactions.Our early studies established that the combination of potassium fluoride (KF) and superstoichiometric tetrabutylammonium chloride (Bu4NCl) serves as a cost-effective alternative to CsF for the SNAr fluorination of chloropicolinate substrates. However, these reactions still require elevated temperatures (>130 °C) and afford moderate yields due to competing decomposition of the substrate and product. The need for high temperature is largely due to slow reaction rates resulting from the low concentration of the active fluorinating reagent [anhydrous tetrabutylammonium fluoride (Bu4NF)] under these conditions. To address this issue, we developed several strategies for generating high concentration solutions of anhydrous tetraalkylammonium fluoride in situ by combining fluorine-containing electrophiles (e.g., hexafluorobenzene, acyl fluorides, sulfonyl fluorides) with tetraalkylammonium nucleophiles (R4NCN or R4NOR). These systems enable SNAr fluorination under unusually mild conditions, affording nearly quantitative yield with chloropicolinate substrates at room temperature. However, the high cost of the electrophiles and the generation of large quantities of byproducts in the R4NF-forming step render this approach unsuitable for process scale applications. As an alternative, we next explored anhydrous tetramethylammonium fluoride (Me4NF) for these transformations. This highly reactive fluoride source can be synthesized directly from inexpensive KF and Me4NCl and then dried by heating under vacuum. Unlike Bu4NF, it is not susceptible to Hofmann elimination. As such, anhydrous Me4NF is stable and isolable, as well as highly effective for the room temperature SNAr fluorination of chloropicolinates and other electron deficient substrates.The studies with anhydrous R4NF drew our attention to another challenge associated with traditional SNAr fluorination reactions: their limitation to substrates bearing resonance electron-withdrawing groups. We hypothesized that this challenge could be addressed by circumventing the Meisenheimer intermediate, a canonical mechanistic feature of SNAr fluorination. By designing reactions that involve an alternative concerted delivery of the fluoride to the ipso C(sp2) center, we developed a deoxyfluorination of arylfluorosulfonates using anhydrous Me4NF. This reaction exhibits a broad scope with respect to the aryl electrophile, with substrates bearing both electron-withdrawing (CN, ester, CF3, Cl) and moderately electron donating (phenyl, alkyl) substituents participating in deoxyfluorination. These deoxyfluorination conditions were also expanded to nonaromatic substrates, including aldehydes and benzylic/aliphatic alcohols.This Account concludes by delineating several ongoing challenges and opportunities in this fast-moving field. For instance, one important future direction will be to address the high moisture sensitivity of these transformations. In addition, the application of these new reagents and methods in the synthesis of pharmaceuticals, agrochemicals, and PET imaging agents will continue to test the versatility and functional group compatibility of these methods.