AbstractSynaptic target selection is critical for establishing functional neuronal circuits. The mechanisms regulating target selection remain incompletely understood. We describe a role for the EGF receptor and its ligand Gurken in target selection of octopaminergic Type II neurons in the Drosophila neuromuscular system. Mutants in happyhour, a regulator of EGFR signaling, form ectopic Type II neuromuscular junctions. These ectopic innervations are due to inappropriate target selection. We demonstrate that EGFR signaling is necessary and sufficient to inhibit synaptic target selection by these octopaminergic Type II neurons, and that the EGFR ligand Gurken is the postsynaptic, muscle‐derived repulsive cue. These results identify a new pathway mediating cell‐type and branch‐specific synaptic repulsion, a novel role for EGFR signaling in synaptic target selection, and an unexpected role for Gurken as a muscle‐secreted repulsive ligand. © 2011 Wiley Periodicals, Inc. Develop Neurobiol, 2012