While sulfoximines are nowadays a well established functional group for medicinal chemistry, the properties of sulfilimines are significantly less well studied, and no sulfilimine has progressed to the clinic to date. In this account, the physicochemical and in vitro properties of sulfilimines are reported and compared to those of sulfoximines and other more traditional functional groups. Furthermore, the impact on the physicochemical and in vitro properties of real drug scaffolds is studied in two series of sulfilimine-containing analogs of imatinib and hNE inhibitors. We show that sulfilimines can be chemically and configurationally stable under physiologically relevant conditions and that they are basic and highly polar and thus are often beneficial for solubility and metabolic stability, although at the cost of reduced permeability. We conclude that