Sexually transmitted infections (STI) can have major consequences for the reproductive health of women. Mycoplasma genitalium is a STI that is not as well studied but causes pelvic inflammatory disease (PID) among other complications. Another well-known STI is Chlamydia trachomatis, notorious for its capability to cause infertility. Both C. trachomatis and M. genitalium share some of the same clinical aspects. Parts of the pathogenesis of C. trachomatis and M. genitalium infections are unclear but potential factors are the microbiome and other STIs. The healthy vaginal microbiome is dominated by Lactobacillus spp; these bacteria protect the host against invading bacteria like C. trachomatis and M. genitalium by producing antibacterial compounds and providing a mechanical barrier. A dysbiosis of the vaginal microbiome is characterized by a non-Lactobacillus spp. dominated microbiome, also known as bacterial vaginosis (BV). BV and BV associated bacteria play a role in the pathogenesis of STIs such as C. trachomatis and M. genitalium. The different species of BV associated bacteria have distinct characteristics that could play a role in C. trachomatis and M. genitalium infections. Host factors should also be considered when analysing the interaction of C. trachomatis and M. genitalium and the microbiome. One important factor is the hormonal homeostasis. Oral hormonal contraception influences the vaginal milieu and could influence the infection process of STIs. Overall, this review attempts to give an overview of the pathogenesisof C. trachomatis and M. genitalium infections and the relationship between M. genitalium, C. trachomatis, and the vaginal microbiome.