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Developmental patterning involves the progressive subdivision of tissue into different cell types by invoking different genetic programs. In particular, cell-cell signaling is a universally deployed means of specifying distinct cell fates in adjacent cells. For this mechanism to be effective, it is essential that an asymmetry be established in the signaling and responding capacities of the participating cells. Here we focus on the regulatory mechanisms underlying the role of the neuralized gene and its protein product in establishing and maintaining asymmetry of signaling through the Notch pathway. The context is the classical process of “lateral inhibition” within Drosophila proneural clusters, which is responsible for distinguishing the sensory organ precursor (SOP) and non-SOP fates among adjacent cells. We find that neur is directly regulated in proneural clusters by both proneural transcriptional activators and Enhancer of split basic helix-loop-helix repressors (bHLH-Rs), via two separate cis-regulatory modules within the neur locus. We show that this bHLH-R regulation is required to prevent the early, pre-SOP expression of neur from being maintained in a subset of non-SOPs following SOP specification. Lastly, we demonstrate that Neur activity in the SOP is required to inhibit, in a cell non-autonomous manner, both neur expression and Neur function in non-SOPs, thus helping to secure the robust establishment of distinct cell identities within the developing proneural cluster., Author summary Much of the process of animal development is concerned with giving cells specific instructions as to what type of cell they are to become—their “fate”. Often, it is even necessary to assign very different fates to cells that are adjacent to each other in the tissue. In such cases, cell-to-cell signaling is frequently utilized as the means of distinguishing the cells’ fates. For example, one cell might send a signal to its neighbors that inhibits them from adopting the same fate as itself. Here, it is obviously vital that there is an asymmetry between the “sending” and “receiving” cells in the ability to transmit such a signal. In the fruit fly Drosophila, the gene neuralized encodes a protein that plays a critical role in establishing the capacity to send such an inhibitory signal. The work we describe here reveals specifically how the receiving cells are prevented from acquiring the ability to send the signal. Remarkably, the Neuralized protein itself is deeply involved in this process. Neuralized function in the sending cell generates two distinct mechanisms that inhibit its own activity in the receiving cells.