The meeting and fusion of gametes and the production of offspring are the main goals of sexually reproducing organisms. In internal fertilizers, fertilization success is enhanced by a suite of physiological and (at least in insects) behavioral changes that mated females undergo after copulation and exposure to the male’s ejaculate. However, conflicts within and between the sexes and context-dependent mating strategies maintain genetic variation in some molecules involved in reproduction. As a result, some combinations of female and male genotypes have a higher reproductive success than others; a phenomenon that could contribute to reproductive isolation as well as to idiopathic infertility in humans. Studies using Drosophila melanogaster elucidated several aspects of female x male genetic interactions that influence reproductive success. For example, natural variation linked with male seminal fluid proteins correlates with a male’s performance in sperm competition and his ability to induce egg production in his mate. However, the female’s genetic and molecular contributions to these interactions remain underexplored. I present four projects that have contributed to our understanding of the female’s side of female x male interactions. First, I employed natural variation in D. melanogaster in combination with transcriptome measurements to identify genes in females whose transcript levels are either altered by mating in general or are altered by mating in a female x male genotype-dependent manner. These experiments indicated that the transcript levels of immune response genes and genes with neuronal functions are especially sensitive to female x male genotype interactions. Second, my collaborator and I showed that these same groups of genes are also sensitive to interactions between the female’s microbiome and her mating status, indicating that not only genotype, but also environment (in this case the microbiome) can influence female x male interactions. Further, using transcriptome data, I detected male RNAs that were transferred to the female during mating. Finally, in a separate project, using sperm competition assays and tissue-specific candidate gene knockdown, my colleagues and I identified genes and neurons in females that influenced the paternity success of the first vs. second male a female mated with. Collectively, the results presented in this thesis encourage further investigation of RNAs in the male’s ejaculate and suggest that the female’s immune system and nervous system act as an important interface between the female and her mate.