The fruit fly, Drosophila melanogaster, has greatly contributed to the advancement of basic biology and medicine over the last century. Forward genetic approaches in Drosophila have been a powerful method to identify novel genes in a genetic pathway of interest. In addition, isolation of new alleles of well-characterized genes from such screens can lead to unexpected and exciting findings. Over the last ten years, we, in Hugo Bellenüfs Laboratory, have been performing large scale screens by combining classical chemical mutagenesis with contemporary FLP/FRT-mediated mitotic recombination technique to isolate and characterize new mutations in essential genes in order to investigate their functions in the nervous system. In the past five years, we have been successful in applying this strategy to the fly X chromosome, a chromosome that has unique constrains when working with essential genes. From this recent screen, we have identified >150 genes that are involved in neuronal development, function and maintenance. Interestingly, a number of these genes have human homologs that have been linked to diverse developmental, neurological and/or metabolic diseases. One example of such gene is Notch which encodes a large transmenbrane receptor of an evolutionarily conserved signaling pathway. Through this seminar, I hope to provide an overview of our recent screen in the Bellen lab, and further discuss our work on new Notch alleles to emphasize the power of Drosophila forward genetics in the modern era of molecular medicine.