Cell-cell adhesion is a fundamental requirement for all multicellular organisms. The calcium-independent cell adhesion molecules of the immunoglobulin superfamily (IgSF-CAMs) represent a major subgroup. They consist of immunoglobulin folds alone or in combination with other protein modules, often fibronectin type-III folds. More than 100 IgSF-CAMs have been identified in vertebrates and invertebrates. Most of the IgSF-CAMs are cell surface molecules that are membrane-anchored either by a single transmembrane segment or by a glycosylphosphatidylinositol (GPI) anchor. Some of the IgSF-CAMs also occur in soluble form, e.g., in the cerebrospinal fluid or in the vitreous fluid of the eye, due to naturally occurring cleavage of the GPI anchor or the membrane-proximal peptide segment. Some IgSF-CAMs, such as NCAM, occur in various forms that are generated by alternative splicing. This unit contains a series of protocols that have been used to study the function of IgSF-CAMs in vitro and in vivo. Curr. Protoc. Cell Biol. 61:9.5.1-9.5.85. © 2013 by John Wiley & Sons, Inc.