Despite numerous investigations, the important structural features of Cell Penetrating Peptides (CPPs) remain unclear as demonstrated by the difficulties encountered in designing new molecules. In this study, we focused our interest on Penetratin and Transportan and several of their variants. Penetratin W48F and Penetratin W48F/W56F exhibit a reduced and a complete lack of cellular uptake, respectively; TP07 and TP10 present a similar cellular uptake as Transportan and TP08, TP13 and TP15 display no or weak internalization capacity. We applied the algorithmic method named PepLook to analyze the peptide polymorphism. The study reveals common conformational characteristics for the CPPs and their permeable variants: they all are polymorphic. Negative, non permeable, mutants share the opposite feature since they are monomorphic. Finally, we support the hypothesis that structural polymorphism may be crucial since it provides peptides with the possibility of adapting their conformation to medium hydrophobicity and or to partner diversity.