Nanoparticles with widely varying physical properties and origins (spherical versus irregular, synthetic versus biological, organic versus inorganic, flexible versus rigid, small versus large) have been previously noted to translocate across the cell plasma membrane. We have employed atomic force microscopy to determine if the physical disruption of lipid membranes, formation of holes and/or thinned regions, is a common mechanism of interaction between these nanoparticles and lipids. It was found that a wide variety of nanoparticles, including a cell penetrating pepide (MSI-78), a protein (TAT), polycationic polymers (PAMAM dendrimers, pentanol-core PAMAM dendrons, polyethyleneimine, and diethylaminoethyl-dextran), and two inorganic particles (Au-NH 2, SiO 2 -NH 2 ), can induce disruption, including the formation of holes, membrane thinning, and/or membrane erosion, in supported lipid bilayers.