Mathematical manipulative models have had a long history of influence in biological research and in secondary school education, but they are frequently neglected in undergraduate biology education. By linking mathematical manipulative models in a four-step process--1) use of physical manipulatives, 2) interactive exploration of computer simulations, 3) derivation of mathematical relationships from core principles, and 4) analysis of real data sets--we demonstrate a process that we have shared in biological faculty development workshops led by staff from the BioQUEST Curriculum Consortium over the past 24 yr. We built this approach based upon a broad survey of literature in mathematical educational research that has convincingly demonstrated the utility of multiple models that involve physical, kinesthetic learning to actual data and interactive simulations. Two projects that use this approach are introduced: The Biological Excel Simulations and Tools in Exploratory, Experiential Mathematics (ESTEEM) Project (http://bioquest.org/esteem) and Numerical Undergraduate Mathematical Biology Education (NUMB3R5 COUNT; http://bioquest.org/numberscount). Examples here emphasize genetics, ecology, population biology, photosynthesis, cancer, and epidemiology. Mathematical manipulative models help learners break through prior fears to develop an appreciation for how mathematical reasoning informs problem solving, inference, and precise communication in biology and enhance the diversity of quantitative biology education. (Contains 13 figures.)