Synthetic methodologies that allow access to new chemical spaces are of paramount importance to modern drug discovery. Fluorine-containing compounds represent a unique chemical space that has caused a fundamental paradigm change in life science research over the past 50 years. There is a significant gap, however, between the needs of the chemical industry and the current methodological efficiency of incorporating fluorinated moieties into organic compounds. To bridge this gap, one of our research programs aims to develop novel reagents and general transformations for the synthesis of fluorinated compounds. In this lecture, I will present our recent efforts to establish mild and operationally simple reactions for the installation of understudied trifluoromethoxy (OCF3) group and polyfluoroalkoxy (ORf) groups into organic molecules. These groups are appealing as they can often enhance molecular efficacy by increasing metabolic stability, promoting binding affinity with targets, and improving cellular membrane permeability of the parent compounds. Nevertheless, due to the lack of general synthetic methods for the introduction of these fluorinated groups, their potential has not been fully exploited in pharmaceutical, agrochemical, and materials applications. Thus, we hope that our research program will allow access to and study of unexplored chemical spaces to aid the discovery and development of new drugs, biocompatible materials, bio-probes, and imaging agents.