The unfavorable crossing of cell membranes by water-soluble peptides poses a challenge to peptide-based drug delivery. Thus the authors engineered a conformational switch that modulates cellular translocation. The peptide design hinges on dehydration propensities of hydrogen bonds that form to mitigate polar-group internalization penalties and is experimentally corroborated through cell-internalization assays. (c) 2007 American Institute of Physics.