Although peptides have not generally been regarded as being membrane permeable, several research groups have shown recently that many small, cyclic peptides are capable of crossing biological membranes. These observations are driving interest in developing small, head-tail cyclic peptides as orally active drugs. In this work, we set out to determine the predominant mechanism of permeation for the membrane permeable peptides reported by Lokey et al. (e.g. cyclo[D-Leu-Leu-Leu-Leu-D-Pro-Tyr]). We have combined experimental data (PAMPA permeability and structures from NMR spectroscopy) with extensive replica-exchange molecular dynamics (MD) simulations to investigate the role of particular conformations in the water and membrane phases. Specifically, we have asked the following questions: 1) Does the membrane conformation of the cyclic peptide pre-exist in aqueous solution? 2) Does the water conformation of the cyclic peptide pre-exist in the membrane? And 3) if either of the previous points are true, can we use this information to estimate the permeability of a particular peptide?