The processes that underlie mate choice have long fascinated biologists. With the advent of increasingly refined genetic tools, we are now beginning to understand the genetic basis of how males and females discriminate among potential mates. One aspect of mate discrimination of particular interest is that which isolates one species from another. As behavioral isolation is thought to be the first step in speciation, and females are choosy more often than males in this regard, identifying the genetic variants that influence interspecies female mate choice can enhance our understanding of the process of speciation. Here, we review the literature on female mate choice in the most widely used model system for studies of species isolation Drosophila. Although females appear to use the same traits for both within- and between-species female mate choice, there seems to be a different genetic basis underlying these choices. Interestingly, most genomic regions that cause females to reject heterospecific males fall within areas of low recombination. Likely, candidate genes are those that act within the auditory or olfactory system, or within areas of the brain that process these systems.