Publisher Summary This chapter discusses all interactions that may be regarded as ligand–receptor interactions, and the methods that have been used to study them. Macromolecular interactions can be classified into ligand–receptor interactions, lectin–sugar interactions, antigen–antibody interactions, GroEL–substrate interactions, lipid–protein interactions, force anchoring proteins to the membrane, receptor mapping, protein unanchoring and identification, and membrane breaking. One major purpose of using atomic force microscope (AFM) for force measurement is to quantify the strength of ligand–receptor interaction forces under physiological conditions. Ligand–receptor Interactions are exemplified by biotin–avidin interaction, interaction of synaptic-vesicle fusion proteins, and interaction between transferrin and its membrane receptor. Antigen–antibody interaction has been studied extensively by using AFM. Proteins with a high affinity to lipids are found in serum as lipoproteins and in biomembranes as intrinsic membrane proteins. Little mechanical work has been done on lipoproteins, but quite a few articles have been published on the measurement of the anchoring force of membrane proteins to the lipid bilayer. Membrane proteins are classified into two groups, the extrinsic and intrinsic membrane proteins. Direct measurement of the thermodynamic affinity of the intrinsic membrane protein to the lipid bilayer membrane is difficult because the solubility of the intrinsic membrane proteins is quite small. However, it is possible to measure the force to extract such proteins from the membrane by the application of a tensile force by using AFM.