Self-avoidance, the tendency of neurites of the same cell to selectively avoid each other, is a property of both vertebrate and invertebrate neurons. In Drosophila, self-avoidance is mediated by a large family of cell recognition molecules of the immunoglobulin superfamily encoded, via alternative splicing, by the Dscam1 locus. Dscam1 promotes self-avoidance in dendrites, axons, and prospective postsynaptic elements. Expression analysis suggests that each neuron expresses a unique combination of isoforms. Identical isoforms on sister neurites exhibit isoform-specific homophilic recognition and elicit repulsion between processes, thereby promoting self-avoidance. Although any isoform can promote self-avoidance, thousands are necessary to ensure that neurites readily discriminate between self and nonself. Recent studies indicate that a large family of cadherins in the mouse, i.e., the clustered protocadherins, functions in an analogous fashion to promote self-avoidance. These studies argue for the evolution of a common molecular strategy for self-avoidance.