Advances in technologies for molecular observation are leading to novel types of data, including gene, transcript, protein, and metabolite levels, which are fundamentally different from the types traditionally compared with microbial ecosystem models, such as biomass (e.g., chlorophyll a) and nutrient concentrations. A grand challenge is to use these data to improve predictive models and use models to explain observed patterns. This article presents a framework that aligns observations and models along the dimension of abstraction or biological organization—from raw sequences to ecosystem patterns for observations, and from sequence simulators to ecological theory for models. It then reviews 16 studies that compared model results with molecular observations. Molecular data can and are being combined with microbial ecosystem models, but to keep up with and take advantage of the full scope of observations, models need to become more mechanistically detailed and complex, which is a technical and cultural challenge for the ecological modeling community.