L1CAM is a neural cell adhesion molecule (CAM) that is critical for proper CNS development in humans. It mediates a myriad of activities important to CNS maturation, including neurite outgrowth, adhesion, fasciculation, migration, myelination and axon guidance. L1CAM promotes these cellular activities by interacting with a diverse group of CAMs, extracellular matrix molecules and signaling receptors through interactions involving its extracellular region. This region is composed of 11 tandem immunoglobulin-like (Ig) domains. This review focuses on the L1CAM extracellular region, and how recent work has clarified important aspects of its structure and function. These studies have provided new insights into how L1CAM binds to several different extracellular molecules, how these binding activities are regulated, and how L1CAM initially folds. Furthermore, these studies suggest that the extracellular region is a dynamic, integrated structure that depends on cooperative interactions among its Ig-like domains for proper functioning.