Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, N-trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of N-trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties. We show that N-trifluoromethyl amines are prone to hydrolysis, whereas N-trifluoromethyl azoles have excellent aqueous stability. Compared to their N-methyl analogues, N-trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, N-trifluoromethyl azoles can serve as bioisosteres of N-iso-propyl and N-tert-butyl azoles. Consequently, we suggest that N-trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry.