Reproductive traits evolve rapidly at the morphological, physiological and molecular levels, a taxonomically robust pattern that is thought to arise from sexual selection. In internally fertilizing organisms, female promiscuity results in competition between multiple male ejaculates for fertilizations in the same female reproductive tract, extending sexual selection past courtship and copulation. In this post-copulatory arena, biochemical interaction between male ejaculates and female reproductive tracts form a dynamic molecular interface that modulates female post-mating responses essential to reproductive fitness. Consistent with the hypothesis that these interactions are subject to sexual selection, sperm and seminal proteins are known to evolve rapidly in a broad range of taxa. The female role in this process, however, in terms of both molecular mechanisms and evolutionary dynamics, remains unclear.The presented dissertation research examines the biochemical nature and evolutionary consequences of post-copulatory sexual selection in two sister-species of cactophilic Drosophila, D. mojavensis and D. arizonae. I first present data that female post-mating response in crosses between these to species is perturbed, severely reducing the reproductive output of heterospecific crosses. A breakdown of reproductive tract interactions in matings between divergent lineages suggests that male and female contributions to reproductive outcomes are coadapted. Next, I use a combination of bioinformatic analyses, comparative sequence analyses, and biochemical assays to elucidate candidate female reproductive tract proteins that may be involved in ejaculate-female dynamics. 241 candidate female reproductive proteins are identified, the most intriguing of which are recently-duplicated secreted proteases. Finally, I explore the evolutionary history of two families of secreted proteases within geographically isolated populations of D. mojavensis. I show that both families evolve rapidly through a complex process involving gene duplication, gene conversion, pseudogenation and positive selection, a unique pattern never before documented in reproductive proteins.Collectively, my dissertation research suggests that females are active participants in the evolution of reproductive tract interactions. Further exploration of how sexual reproduction coevolves between males and females, both in terms of interacting biomolecules, and dynamic evolutionary histories, remains an important challenge for future research.