In the past 5 years, hexafluoroisopropanol (HFIP) has been used as a unique solvent or additive to enable challenging transformations through substrate activation and stabilization of reactive intermediates. In this Review, we aim at describing difunctionalization processes which were unlocked when HFIP was involved. Specifically, we focus on cyclizations and additions to alkenes, alkynes, epoxides, and carbonyls that introduce a wide range of functional groups of interest., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)