MPs have been shown to be capable of engaging difficult-to-drug proteins with shallow binding pockets but the relatively poor membrane permeability and bioavailability of most MPs have limited their utility in addressing intracellular targets. Therefore, there is a high degree of interest in the discovery of novel MPs with improved pharmacokinetic properties. Several investigators have developed variants of cellpenetrating peptides to solve this problem. These are cationic oligomers that are thought to bind to the plasma membrane and trigger the formation of an endocytotic vesicle. This is very different from achieving passive permeability in that the MP must eventually escape from the endosome. While there has been significant progress in this vein, 24 there is lingering concern about toxicity in employing this mechanism of action to gain entry of MPs into cells.