A key aspect of membrane targeting and cycling of dually lipidated proteins such as H/N-Ras, and the compartment where palmitoylation occurs, is the membrane interaction dynamics of the monofarnesylated protein. It is often implied that peripheral proteins bind to all or any intracellular membrane before palmitoylation; but is this the case? Does farnesylated Ras have an equal affinity for all intracellular membranes and, therefore, an unbiased membrane sampling before palmitoylation? In vitro experiments suggest that this may not be the case, as membrane interactions of farnesylated peptides are affected by membrane lipid composition (Gohlke et al., 2010) . Binding of farnesylated N-Ras to liquidordered membranes containing saturated phospholipids and cholesterol was reduced compared with liquid-disordered membranes made from an unsaturated phospholipid. These findings are particularly relevant given the high concentration of cholesterol in the plasma and endosomal membranes compared with membranes such as the ER (Mondal et al., 2009) . Semisynthetic proteins containing a single farnesyl or myristoyl group were suggested to interact with the plasma membrane based on total internal fluorescence microscopy analysis ; however, there was no indication of whether this interaction occurred with the same efficiency as interaction with ER-Golgi membranes. Visual inspection of the localization of farnesylated Ras proteins and peptides expressed in cells via plasmid transfection reveals clear ER and Golgi staining, whereas interaction with other membrane compartments (including the plasma membrane) is less obvious (Choy et al., 1999; Rocks et al., 2005 Rocks et al., , 2010 . Therefore, peripheral proteins may display a preference for interaction with specific membrane compartments rather than binding randomly to any intracellular membrane. This would clearly provide palmitoylation-dependent protein cycling with more specificity and directionality. The precise membrane interaction dynamics of peripheral proteins before palmitoylation therefore merits further high-resolution analysis.