SynCAMs (Synaptic Cell Adhesion Molecules) are crucial for synapse formation and plasticity. However, we demonstrated that SynCAMs were also required during earlier stages of neural circuit formation, as SynCAM1 and SynCAM2 were shown to be important for the guidance of post-crossing commissural axons. In contrast to the exclusively homophilic cis-interactions reported by previous studies, our in vivo results suggested the existence of heterophilic cis-interactions between SynCAM1 and SynCAM2. Indeed, as we show here, the presence of homo- and heterophilic cis-interactions modulates the interaction of SynCAMs with trans-binding partners, as observed previously for other immunoglobulin superfamily cell adhesion molecules. These in vitro findings are in agreement with results from in vivo studies, which demonstrate a role for SynCAMs in the formation of sensory neural circuits in the chicken embryo. In the absence of SynCAMs selective axon-axon interactions are perturbed resulting in aberrant pathfinding of sensory afferents.