Purification and study of transmembrane proteins require isolation of these structures from their lipid environment. This isolation is carried out through the use of detergents. In this unit, several approaches to solubilization of membrane proteins are presented. Solubilization of whole lymphocytes, using conditions aimed at minimizing the disruption of protein-protein interactions, is described with an optional step that may be useful when the disruption of protein interactions is desired as part of a purification protocol. In some situations, it may be desirable to purify membranes prior to their solubilization or to determine the physical relationship between proteins, which can be accomplished by a cross-linking.