Drosophila melanogaster has the longest history as a genetic model system and even in the present day remains the front runner in diverse fields of biology. However, lack of a convenient method to make specified modifications to endogenous genes has been a pain in the neck for many fly geneticists for decades. Synthetic nuclease technologies, especially the CRISPR/Cas9 system, hold great promise for a breakthrough. Synthetic nucleases are programmable nucleases that can be directed to cleave a specified sequence in the genome. Deleterious mutations can be efficiently induced by expression of a synthetic nuclease that targets a gene of interest. Precise modification of the target site, such as a reporter gene knock-in, is also possible by simultaneous delivery of a synthetic nuclease and a targeting vector. Here I summarize recent advances in synthetic nuclease technologies and discuss their possible applications to Drosophila genetics.