Glycans are sugar molecules present ubiquitously in all living organisms. Their abnormal expression in diseases such as cancer, use by pathogens to infect host cells, and roles in the immune system makes them important targets for the design of therapeutics and diagnostics. However, a major limitation in targeting the vast array of glycans has been the lack of reliable reagents. Many existing glycan-binding proteins exhibit broad specificity, low affinity, and are costly to produce. Thus, there is an urgent need for a rapid, high-throughput platform that can produce high-affinity glycan-binding proteins. We discuss the design of one such platform based on the directed evolution of alternative protein scaffold libraries using yeast surface display. A library of the tenth repeat, type III domain of human fibronectin (FN3) was screened against polysialic acid, a glycan found in certain cancers, and enriched using a combination of random mutagenesis, magnetic-activated cell sorting, and fluorescence-activated cell sorting. The population of isolated binders was characterized by yeast surface titrations. We were able to demonstrate the concentration of binders to therapeutically relevant affinities in the low nanomolar range. Future modifications to the platform will build upon this work to further enhance the specificity of binders towards glycans. The success of this platform will allow rapid investigation of multiple protein libraries to produce high-affinity, high specificity glycan-binding reagents for use in applications such as imaging and targeted therapeutics.