The vaginal microbiome (VMB) is critical to female reproductive health; however, the mechanisms associated with optimal and non-optimal states remain poorly understood due to the complex community structure and dynamic nature. Quantitative systems biology techniques applied to the VMB have improved understanding of community composition and function using primarily statistical methods. In contrast, fewer mechanistic models that use a priori knowledge of VMB features to develop predictive models have been implemented despite their use for microbiomes at other sites, including the gastrointestinal tract. Here, we explore systems biology approaches that have been applied in the VMB, highlighting successful techniques and discussing new directions that hold promise for improving understanding of health and disease.