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Establishing precise midline circuitry is essential to control rhythmic and locomotor behaviors. Conserved signals that regulate axon guidance at the midline include attractive cues such as Netrins, and repulsive cues such as Slits, Semaphorins and Ephrins. In Drosophila, Netrin attracts many commissural axons to the midline through activation of the Frazzled (Fra)/DCC (Deleted in Colorectal Cancer) receptor, while the repellant Slit and its receptor Roundabout (Robo) prevent commissural axons from re-crossing. Commissureless (Comm) controls midline crossing by negatively regulating surface levels of Robo on pre-crossing commissural axons. In this seminar recent findings that contribute to our understanding of how signals are coordinated at the midline to control commissural axon guidance will be presented. In addition, how different Robo receptors mediate distinct axon guidance decisions to regulate midline connectivity will be highlighted.