During development, axons must integrate directional information encoded by multiple guidance cues and their receptors. Axon guidance receptors, such as UNC-40 (DCC) and SAX-3 (Robo), can function individually or combinatorially with other guidance receptors to regulate downstream effectors. However, little is known about the molecular mechanisms that mediate combinatorial guidance receptor signaling. Here, we show that UNC-40, SAX-3 and the SYD-1 RhoGAP-like protein function interdependently to regulate the MIG-2 (Rac) GTPase in the HSN axon of C. elegans. We find that SYD-1 mediates an UNC-6 (netrin) independent UNC-40 activity to promote ventral axon guidance. Genetic analysis suggests that SYD-1 function in axon guidance requires both UNC-40 and SAX-3 activity. Moreover, the cytoplasmic domains of UNC-40 and SAX-3 bind to SYD-1 and SYD-1 binds to and negatively regulates the MIG-2 (Rac) GTPase. We also find that the function of SYD-1 in axon guidance is mediated by its phylogenetically conserved C isoform, indicating that the role of SYD-1 in guidance is distinct from its previously described roles in synaptogenesis and axonal specification. Our observations reveal a molecular mechanism that can allow two guidance receptors to function interdependently to regulate a common downstream effector, providing a potential means for the integration of guidance signals., Author Summary The nervous system is comprised of a complex network of axonal connections. This network is formed during development, when axons navigate to their target regions. Axon navigation requires multiple signaling pathways to detect and respond to extracellular guidance cues. Many of the guidance cues, receptors and signaling pathways have been identified. However, little is known about how the information encoded by different guidance cues is combined to arrive at a directional response. A key part of how this occurs is likely to involve combinatorial receptor signaling, when different guidance receptors work in combination with each other. However, the mechanisms that underlie combinatorial receptor signaling remain mostly unknown. In C. elegans, ventral axon guidance is mediated by the UNC-40 (DCC) and SAX-3 (Robo) guidance receptors. Here, we use genetic and biochemical analysis to identify a molecular mechanism that can mediate combinatorial signaling involving UNC-40, SAX-3 and the RhoGAP-like protein SYD-1.