It is well documented that membrane binding of MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate) requires both hydrophobic insertion of the N-terminal myristate into the bilayer and electrostatic interaction of the basic effector region with acidic lipids. The structure of a membrane-bound peptide corresponding to the effector region, residues 151-175 of bovine MARCKS, was recently determined using spin-labeled peptides and EPR. The kinetics of the peptide-membrane interaction were determined from stopped-flow fluorescence measurements; the adsorption of the peptide onto phospholipid vesicles is a diffusion-limited process. Five microM Ca2+-calmodulin decreases the lifetime of the peptide on a 100 nm diameter 10:1 PC/PS vesicle from 0.1 s to 0.01 s by rapidly pulling the peptide off the membrane. We propose a molecular mechanism, based on previous work by M. Eigen and colleagues, by which calmodulin may remove MARCKS(151-175) from the membrane at a diffusion-limited rate. Calmodulin may also use this mechanism to remove the pseudosubstrate region from the substrate binding site of enzymes such as calmodulin kinase II and myosin light chain kinase.