The protein family known as CLAMS (cholinesterase-like adhesion molecules) forms a novel class of heterophilic cell adhesion proteins. Family members are found through a wide range of metazoans and play a role during the development of multiple tissues. The majority of members of this family are transmembrane proteins with an extracellular domain that is conserved with cholinesterases including acetylcholinesterase. Yet all family members lack one or more of the residues that make up the catalytic triad necessary for enzymatic function. Therefore the conserved cholinesterase-like domain is not necessary for enzymatic function but does appear to play a role in heterophilic binding. CLAMS are expressed in a wide array of tissues and most family members appear to play a role in cell adhesion and junction formation. The development of junctions including septate junctions and synaptic junctions require CLAM family members such as Gliotactin and Neuroligins respectively. Modeling of the cholinesterase-like domain reveals that evolutionary changes to the binding pocket of the cholinesterase domain may produce a range of different ligand binding partners for CLAM family members. In this vein, previous chimera experiments and recent work has identified mutations in CLAM family members that affect the structure of the cholinesterase-like domain. These mutant forms affect protein function during the development of specialized junctions and confirm the role of the cholinesterase domain in mediating heterophilic binding.