When axons grow towards their targets, their tips form a specialized dynamic structure called the growth cone. To establish their orientation, growth cones continuously explore their local environment for guidance information. The growth cone sensor for immobilized signals displayed on the surface of cells or in the extracellular matrix is a multimolecular complex of surface molecules, signaling molecules and cytoskeletal components. Axonin-1 and neuron-glia cell-adhesion molecule (NgCAM) are thought to play an important role as surface-expressed "recognition" components of the pathway sensor of the growth cones in a number of neuronal populations of the peripheral and central nervous systems. Both molecules are capable of specifically binding a number of other extracellular molecules and cluster at the substratum contact area of the growth cone, when the substratum contains axonin-1 or NgCAM. Recent results indicate that axonin-1 and NgCAM interact in the plane of the growth cone membrane and that their clustering is associated with a change in the associated intracellular signals. The present review summarizes the recent developments of the concept that different clusters of axonin-1 and NgCAM at growth cone/substratum contacts elicit different intracellular signals in growth cones and eventually determine the pathway choice of the growth cone.