Synthetic insecticides have been used intensively for the past 50 years in many parts of the world. Insect populations, both target and nontarget, have responded by evolving resistance. One of the nontarget insects is Drosophila melanogaster, which is well-suited for genetic analysis and has been particularly well-studied in both laboratory and field populations. Resistance to several insecticides, including two for which significant resistance in field populations has not been found, has been generated in susceptible laboratory strains following mutagenesis, allowing comprehensive study of the resistance genes. Field populations of D. melanogaster have evolved resistance to many, but not all, insecticides in use today. Both the genetic and biochemical mechanisms that underlie resistance in this insect are similar to those in other insects. Therefore, D. melanogaster can be a sentinel organism for long-term release of toxicants into the environment. While it remains useful for genetic analysis of resistance, a better understanding of the movement and population structures of this insect will be a prerequisite for its sentinel utilization at specific locales.