Fluorographene (FG) is a two-dimensional graphene derivative with promising application potential; however, its reactivity is not understood. We have systematically explored its reactivity in vacuum and polar environments. The C−F bond dissociation energies for homo-and heterolytic cleavage are above 100 kcal/mol, but the barrier of S N 2 substitution is significantly lower. For example, the experimentally determined activation barrier of the FG reaction with NaOH in acetone equals 14 ± 5 kcal/mol. The considerable reactivity of FG indicates that it is a viable precursor for the synthesis of graphene derivatives and cannot be regarded as a chemical counterpart of Teflon.