Biological membranes exhibit a bilayer arrangement of lipid molecules forming a hydrophobic core that presents a physical barrier to all polar and charged species. This universally accepted view has been challenged by biophysical partitioning experiments that suggest small free energies to insert charged side chains into the center of a membrane. We survey theoretical, experimental and simulation approaches and report free energy simulations that reveal large barriers for charged side chain movement across membranes. In simulations of an arginine side chain attached to a transmembrane α-helix and its simple side chain analog molecule, significant penetration of water and lipid head groups into the membrane core is seen. Yet there exists differences in the shape and magnitude of the free energy profiles due to the presence of the host helix. Calculated p Ka shifts within the membrane suggest that arginine will remain mostly protonated throughout the membrane if attached to a transmembrane helix. The discrepancy between simulation and a recent translocon-based assay is explained in terms of several factors, including the difficulties in obtaining a spatial interpretation from these experiments. These simulations have implications for the gating mechanisms of voltage gated ion channels, suggesting that large paddle-like movements of lipid-exposed arginines are unlikely.