ABSTRACT Biological systems are inherently complex, and the increasing level of detail with which we are able to experimentally probe such systems continually reveals new complexity. Fortunately, mathematical models are uniquely positioned to provide a tool amenable for rigorous analysis, hypothesis generation, and connecting results from isolated in vitro experiments with results from in vivo and whole organism studies. However, developing useful mathematical models is challenging because of the often different domains of knowledge required in both math and biology. In this work, we endeavor to provide a useful guide for researchers interested in incorporating mathematical modeling into their scientific process. We advocate for the use of conceptual diagrams as a starting place to anchor researchers from both domains. These diagrams are useful for simplifying the biological process in question and distinguishing the essential components. Not only do they serve as the basis for developing a variety of mathematical models but they ensure that any mathematical formulation of the biological system is led primarily by scientific questions. We provide a specific example of this process from our own work in studying prion aggregation to show the power of mathematical models to synergistically interact with experiments and push forward biological understanding. Choosing the most suitable model also depends on many different factors and we consider how to make these choices based on different scales of biological organization and available data. We close by discussing the many opportunities that abound for both experimentalists and modelers to take advantage of collaborative work in this field.